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HIV Treatment Research and Key Takeaways: Dr. Dieffenbach’s Final Update from CROI 2024

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On Wednesday as the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) was winding down, HIV.gov spoke with NIH’s Dr. Carl Dieffenbach about highlights of long-acting HIV treatment research discussed at the conference. Dr. Dieffenbach is the Director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Diseases . He spoke with Brian Minalga, MSW, Deputy Director of the NIH-supported  Office of HIV/AIDS Network Coordination Exit Disclaimer . Watch our conversation with Dr. Dieffenbach below:

Research Suggests Possible Expanded Options for Long-Acting HIV Treatment

Dr. Dieffenbach highlighted findings from several clinical trials and a plenary session presented at CROI about current and future options for long-acting antiretroviral treatment (ART) for HIV.

First, he discussed a NIAID-supported randomized clinical trial that found that long-acting ART with cabotegravir and rilpivirine was superior in suppressing HIV replication compared to daily oral ART in adults who had been unable to maintain viral suppression through an oral daily regimen. The LATITUDE study Exit Disclaimer enrolled participants in 31 sites in the United States. Last month, the trial’s Data and Safety Monitoring Board conducted a planned review of interim data and recommended halting randomization and offering all eligible study participants long-acting ART based on its observed superior viral suppression of HIV. At CROI, study leaders reported that the interim analysis of data from 294 participants showed that the chance of experiencing unsuppressed HIV was 7% among people taking long-acting ART compared to 25% among those taking daily oral ART . The likelihood of discontinuing the assigned regimen due to adverse events or experiencing unsuppressed HIV was 10% among people taking long-acting ART compared to 26% among those taking daily ART. These findings were statistically significant. Dr. Dieffenbach observed that these results may support expanding the use of long-acting ART among a broader population. Read the study abstract Exit Disclaimer . Read more in this NIAID news release .

Another ongoing clinical trial reported initial findings on the safety of the same long-acting injectable treatment regimen for adolescents with HIV with a suppressed viral load. The NIH-supported MOCHA study Exit Disclaimer enrolled participants aged 12 to 17 who were virally suppressed in Botswana, South Africa, Thailand, Uganda, and the United States. In what he characterized as very encouraging results, Dr. Aditya Gaur of St. Jude Children's Research Hospital, one of the trial’s co-chairs, reported that after the first six months all participants remained virally suppressed, and the level of the ART in their systems was comparable to what has been shown as efficacious in adult studies of the same drug . He also reported that, while about one-third of the participants reported an injection-site reaction, there were no surprising or unanticipated adverse events. These data support the use of cabotegravir and rilpivirine in virally suppressed adolescents, according to Dr. Gaur and colleagues. Dr. Dieffenbach noted that NIH will continue to support safety and dosing studies to determine the proper doses for adolescents and that these studies could eventually expand access to this long-acting HIV treatment to more people. Read the abstract Exit Disclaimer . Read NIAID’s news release about the study .

In addition, Dr. Dieffenbach mentioned an industry-sponsored Phase 2 trial that presented 24-week results of an oral once-weekly investigational combination of two drugs ( islatravir and lenacapavir ). Researchers reported that the investigational combination maintained a high level of viral suppression among study participants and was well tolerated. The study will continue to gather data and suggests that a weekly oral HIV treatment regimen could someday be possible . Read the abstract Exit Disclaimer .

Finally, Dr. Dieffenbach discussed Wednesday’s plenary session by Dr. Charles Flexner of The Johns Hopkins University School of Medicine, which was titled “The End of Oral? How Long-Acting Formulations Are Changing the Management of Infectious Diseases.” In his big picture, future-focused presentation exploring long-acting drug delivery, Dr. Flexner observed that there is a need for HIV products with less frequent dosing, greater convenience, and greater likelihood of viral suppression, as well as for the prevention and treatment of other diseases, including tuberculosis, malaria, and viral hepatitis. He discussed recent advances in formulation science that are going to help make available better replacements for daily oral drugs for HIV and many other infectious diseases . Dr. Dieffenbach underscored Dr. Flexner’s point that these novel products must be developed with access and equity in mind so that people who need them, especially in resource-limited settings, can use them.

Key Takeaways

Reflecting on key takeaways from the entire conference, both Dr. Dieffenbach and Brian pointed to the importance of partnership between the HIV community and scientists in all aspects of HIV research , a theme also discussed in HIV.gov’s conversation with Dr. LaRon Nelson from the conference. In terms of research highlights, Dr. Dieffenbach pointed to the results reported from the IMPAACT P1115 study in which several children who started HIV treatment within hours of birth later surpassed a year of HIV remission after a treatment pause. ( See HIV.gov’s interview with Dr. Deborah Persaud about this study .) He also noted that the additional data accumulating on the effectiveness of Doxy-PEP is encouraging and will hopefully soon be reflected in clinical guidelines that help to reduce the incidence of syphilis, chlamydia, and gonorrhea in men who have sex with men and transgender women.

Catch Up on More HIV Research Updates

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s social media channels and recapped here on the blog this week and next week.

More than 3,600 HIV and infectious disease researchers from 73 countries gathered in Denver and virtually from March 3-6 this year for CROI, an annual scientific meeting on the latest research that can help accelerate global progress in the response to HIV and other infectious diseases, including STIs and viral hepatitis. Over 1,000 summaries of original research were presented. Visit the conference website Exit Disclaimer for more information. Session webcasts and more information will be published there for public access in 30 days.

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After decades of failures, researchers have renewed hopes for an effective HIV vaccine

Abstract Mid-Century Geometric Shapes Blue Gray Distorted Scratched Textured Background with vaccine overlay.

The world needs an HIV vaccine if it ever hopes to beat a virus that still infects over 1 million people a year and contributes to hundreds of thousands of deaths.

Despite 20 years of failures in major HIV vaccine trials — four this decade alone — researchers say recent scientific advances have likely, hopefully, put them on the right track to develop a highly effective vaccine against the insidious virus.

But probably not until the 2030s. 

“An effective vaccine is really the only way to provide long-term immunity against HIV, and that’s what we need,” Dr. Julie McElrath, the director of the vaccine and infectious disease division at the Fred Hutchinson Cancer Center in Seattle, said Monday at the Conference on Retroviruses and Opportunistic Infections in Denver.

All current HIV vaccine action is in the laboratory, animal studies or very early human trials.

Researchers at the retrovirus conference presented favorable results from two HIV vaccine studies. One found that a modification to the simian version of HIV spurred production of what are known as broadly neutralizing antibodies against the virus in monkeys. Another showed promise in the effort to coax the immune system’s B cells to make the powerful antibodies in humans. 

“These trials illustrate as a proof of concept that we can train the immune system. But we need to further optimize it and test it in clinical trials,” Karlijn van der Straten, a Ph.D. student at the Academic Medical Center at Amsterdam University, who presented the human study, said at a news conference Monday.

Still, the scrappy scientists in this field face a towering challenge. HIV is perhaps the most complex pathogen ever known. 

“The whole field has learned from the past,” said William Schief, who leads Moderna’s HIV vaccine efforts. “We’ve learned strategies that don’t work.”

The cost has already been immense. Nearly $17 billion was spent worldwide on HIV -vaccine research from 2000 to 2021. Nearly $1 billion more is spent annually, according to the Joint United Nations Program on HIV/AIDS and the nonprofit HIV group AVAC.

“Maintaining the funding for HIV vaccines right now is really important,” said Dr. Nina Russell, who directs HIV research at the Bill & Melinda Gates Foundation. She pointed to the field’s own “progress and the excitement” and to how “HIV vaccine science and scientists continue to drive innovation and science that benefits other infectious diseases and global health in general.” 

Case in point: Covid. Thanks to HIV research, the mRNA vaccine technology was already available in 2020 to speed a coronavirus vaccine to market.

Why the HIV vaccine efficacy trials failed

In strong contrast to Covid, the HIV vaccine endeavor has spanned four decades. Only one of the nine HIV vaccine trials have shown efficacy: a trial conducted in Thailand and published in 2009 that reported a modest 31% reduction in HIV risk.

HIV vaccine researchers subsequently spent years seeking to retool and improve that vaccine strategy, leading to a series of trials that launched in the late 2010s — only to fail.

Researchers have concluded those latest trials were doomed because, aside from prompting an anti-HIV response based in immune cells, they only drove the immune system to produce what are known as non-neutralizing antibodies. Those weapons just weren’t strong enough for such a fearsome foe.

Preventing HIV through vaccination remains a daunting challenge because the immune system doesn’t naturally mount an effective defense against the virus, as it does with so many other vaccine-preventable infections, including Covid. An HIV vaccine must coax from the body a supercharged immune response with no natural equivalent.

That path to victory is based on a crucial caveat: A small proportion of people with HIV do produce what are known as broadly neutralizing antibodies against the virus. They attack HIV in multiple ways and can neutralize a swath of variants of the virus.

Those antibodies don’t do much apparent good for people who develop them naturally, because they typically don’t arise until years into infection. HIV establishes a permanent reservoir in the body within about a week after infection, one that their immune response can’t eliminate. So HIV-positive people with such antibodies still require antiretroviral treatment to remain healthy.

Researchers believe that broadly neutralizing antibodies could prevent HIV from ever seeding an infection, provided the defense was ready in advance of exposure. A pair of major efficacy trials, published in 2021 , demonstrated that infusions of cloned versions of one such antibody did, indeed, protect people who were exposed to certain HIV strains that are susceptible to that antibody. 

However, globally, those particular strains of the virus comprise only a small subset of all circulating HIV. That means researchers can’t simply prompt a vaccine to produce that one antibody and expect it to be effective. Importantly, from this study they got a sense of what antibody level would be required to prevent infection. 

It’s a high benchmark, but at least investigators now have a clearer sense of the challenge before them. 

Also frustrating the HIV vaccine quest is that the virus mutates like mad. Whatever spot on the surface of the virus that antibodies target might be prone to change through mutation, thus allowing the virus to evade their attack. Consequently, researchers search for targets on the virus’ surface that aren’t highly subject to mutation.

Experts also believe warding off the mutation threat will require targeting multiple sites on the virus. So researchers are seeking to develop a portfolio of immune system prompts that would spur production of an array of broadly neutralizing antibodies.

Prompting the development of such antibodies requires a complex, step-by step process of coaxing the infection-fighting B cells, getting them to multiply and then guiding their maturation into potent broadly neutralizing antibody-producing factories.

HIV vaccine development ‘in a better place’

Dr. Carl Dieffenbach, the head of the AIDS division at the National Institute of Allergy and Infectious Diseases, said numerous recent technological advances — including mRNA, better animal models of HIV infection and high-tech imaging technology — have improved researchers’ precision in designing, and speed in producing, new proteins to spur anti-HIV immune responses.

Global collaboration among major players is also flourishing, researchers said. There are several early-stage human clinical trials of HIV-vaccine components underway.

Three mRNA- based early human trials of such components have been launched since 2022. Among them, they have been led or otherwise funded by the global vaccine research nonprofit group IAVI, Fred Hutch, Moderna, Scripps Research, the Gates Foundation, the National Institutes of Health, the U.S. Agency for International Development, and university teams. More such trials are in the works.

On Friday, Science magazine reported concerning recent findings that among the three mRNA trials, a substantial proportion of participants — 7% to 18%, IAVI said in a statement — experienced skin-related symptoms following injections, including hives, itching and welts.

IAVI said in its statement that it and partners are investigating the HIV trials’ skin-related outcomes, most of which were “mild or moderate and managed with simple allergy medications.” 

Researchers have shown success in one of those mRNA trials in executing a particular step in the B-cell cultivation process.

That vaccine component also generated “helper” CD4 cells primed to combat HIV. The immune cells are expected to operate like an orchestra conductor for the immune system, coordinating a response by sending instructions to B cells and scaling up other facets of an assault on HIV.

A complementary strategy under investigation seeks to promote the development of “killer” CD8 cells that might be primed to kill off any immune cells that the antibodies failed to save from infection.

Crucially, investigators believe they are now much better able to discern top vaccine component candidates from the duds. They plan to spend the coming years developing such components so that when they do assemble the most promising among them into a multi-pronged vaccine, they can be much more confident of ultimate success in a trial.

“An HIV vaccine could end HIV,” McElrath said at the Denver conference. “So I say, ‘Let’s just get on with it.”

Dr. Mark Feinberg, president and CEO of IAVI, suggested that the first trial to test effectiveness of the vaccine might not launch until 2030 or later.

Even so, he was bullish.

“The field of HIV vaccine development is in a better place now than it’s ever been,” he said.

new research hiv

Benjamin Ryan is independent journalist specializing in science and LGBTQ coverage. He contributes to NBC News, The New York Times, The Guardian and Thomson Reuters Foundation and has also written for The Washington Post, The Nation, The Atlantic and New York.

  • UNC Chapel Hill

New Trial Highlights Incremental Progress Towards a Cure for HIV-1

February 13, 2024

By Kendall Daniels

A blonde woman sitting on a bench wearing a cream-colored blazer.

CHAPEL HILL, N.C. – Antiretroviral therapies (ART) stop HIV replication in its tracks, allowing people with HIV to live relatively normal lives. However, despite these treatments, some HIV still lingers inside cells in a dormant state known as “latency.” If ART is discontinued, HIV will awaken from its dormant state, begin to replicate, and cause acquired immunodeficiency syndrome (AIDS). To create a cure, researchers have been attempting to drive HIV out of latency and target it for destruction.

A new clinical trial led by Cynthia Gay, MD, MPH , associate professor of infectious diseases, David Margolis, MD , the Sarah Kenan Distinguished Professor of Medicine, Microbiology & Immunology, and Epidemiology, and other clinicians and researchers at the UNC School of Medicine suggests that a combination of the drug vorinostat and immunotherapy can coax HIV-infected cells out of latency and attack them.

The immunotherapy was provided by a team led by Catherine Bollard, MD, at the George Washington University, who took white blood cells from the study participants and expanded them in the laboratory, augmenting the cells’ ability to attack HIV-infected cells, before re-infusion at UNC.

Their results, published in the Journal of Infectious Diseases , showed a small dent on the latent reservoir, demonstrating that there is more work to be done in the field.

“We did show that this approach can reduce the reservoir, but the reductions were not nearly large enough, and statistically speaking were what we call a “trend” but not highly statistically significant,” said David Margolis, MD , director of the HIV Cure Center and senior author on the paper. “We need to create better approaches to flush out the virus and attack it when it comes out. We need to keep chipping away at the reservoir until there’s nothing there.”

Waking up Latent HIV in Our Genes

David Margolis, MD, Director of the UNC HIV Cure Center

DNA inside cell nuclei is kept in a tightly packed space by chromosomes, which act as highly organized storage facilities. When you unfurl a chromosome, you’ll find loop-de-loop-like fibers called chromatin. If you keep unfurling, you’ll see long strands of DNA wrapped around scaffold proteins known as histones, like beads on a string. Finally, when the unfurling is complete, you will see the iconic DNA double helix.

Vorinostat works by inhibiting a lock-like enzyme called histone deacetylase. By stopping this mechanism, tiny doors within the chromatin fibers unlock and open up, effectively “waking up” latent HIV from its slumber and making it vulnerable to an immune system attack. As a result, a tiny blip of HIV expression shows up on very sensitive molecular assays.

But the effects of vorinostat are short lived, only lasting a day per dose. For this reason, Margolis and other researchers are trying to find safe and effective ways to administer the drug and keep the chromatin channels open for longer periods of time.

Attacking Exposed HIV Reservoirs

For the study, six participants were given multiple doses of vorinostat. Researchers then extracted immune cells from the participants and expanded the cells that knew how to attack HIV-infected cells.

This immunotherapy method, which has been successful against other viruses such as Epstein-Barr virus and cytomegalovirus, involves giving participants back their expanded immune cells in the hopes that these cells will further multiply in number and launch an all-out attack on the newly exposed HIV-infected cells.

However, in the first part of this study, only one of the six participants saw a drop in their HIV reservoir levels. To test whether the result was simply random or something more, researchers gave three participants their usual dose of vorinostat, but introduced five times the amount of engineered immune cells. All three of the participants had a slight decline in their reservoirs.

But, statistically speaking, the results were not large enough to be definitive.

“This is not the result we wanted, but it is research that needed to be done,” said Margolis. “We are working on improving both latency reversal and clearance of infected cells, and we hope to do more studies as soon as we can, using newer and better approaches.”

A Dedicated Cohort

Many of the participants in the study have been working with Margolis’s research team for years, sacrificing their own time and blood for research efforts. Their long-term partnership and commitment have been essential for data collection. The data, which follows the size of the viral reservoir in these people over years prior to this study, makes the small changes found more compelling.

“People living with HIV come in a couple of times a year, and we measure residual traces of virus in their blood cells, which doesn’t have any immediate benefit to them,” said Margolis. “It’s a very altruistic action and we couldn’t make any progress without their help.”

Media contact:  Kendall Daniels , Communications Specialist, UNC Health | UNC School of Medicine

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  • Published: 01 December 2021

Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021

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  • Sharon R. Lewin   ORCID: orcid.org/0000-0002-0330-8241 15 , 16 , 17 &

The International AIDS Society (IAS) Global Scientific Strategy working group

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  • Translational research

Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. HIV can integrate in the host genome and persist for the life span of the infected cell. These latently infected cells are not recognized as foreign because they are largely transcriptionally silent, but contain replication-competent virus that drives resurgence of the infection once ART is stopped. With a combination of immune activators, neutralizing antibodies, and therapeutic vaccines, some nonhuman primate models have been cured, providing optimism for these approaches now being evaluated in human clinical trials. In vivo delivery of gene-editing tools to either target the virus, boost immunity or protect cells from infection, also holds promise for future HIV cure strategies. In this Review, we discuss advances related to HIV cure in the last 5 years, highlight remaining knowledge gaps and identify priority areas for research for the next 5 years.

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Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions

Jakub Kopycinski, Hongbing Yang, … RIVER trial study group

Modern antiretroviral regimens can effectively block HIV replication in people with HIV for decades, but these therapies are not curative and must be taken for life. However, there is evidence that a cure can be achieved; initially, this came from a single case study (Timothy Brown, a man living with HIV who became widely known as the ‘Berlin patient’) following bone-marrow transplantation from a donor who was naturally resistant to HIV 1 . On the basis of this inspiring development and the recognition that not everyone can access and/or adhere indefinitely to antiretroviral therapy (ART), a global consensus emerged approximately 10 years ago that a curative intervention was a high priority for people with HIV and would be necessary to bring an end to the HIV pandemic. Since then, there has been a second case report of a cure following bone-marrow transplantation 2 as well as evidence of persistence of only defective forms of the virus in certain patients 3 and enhanced immune control of the virus by others after only a short time on ART 4 —further supporting the notion that a cure for HIV can be achieved.

An HIV cure includes both remission and eradication. Here, we define the term remission as durable control of virus in the absence of any ongoing ART. Eradication is the complete removal of intact and rebound-competent virus. The minimal and optimal criteria for an acceptable target product profile for an HIV cure, including the duration and level of virus control off ART, has recently been developed and published by the International AIDS Society (IAS), following wide consultation with multiple stakeholders 5 .

In 2011 and 2016, the IAS convened expert working groups to outline a strategy for developing an effective and scalable cure 6 , 7 . Since then, significant progress has been made, and the overall agenda has evolved. Here, we assembled a group of experts from academia, industry, and the community (Box 1 ) to evaluate recent progress and to outline cure-related research priorities for the next 5 years. The key recommendations for each component of the strategy are summarized in Box 2 .

Box 1 The Global Cure Strategy—forming a consensus

The Global Cure Strategy was created using a full online process during the COVID-19 pandemic from November 2020 to August 2021. The co-chairs of the initiative identified the major topics which were divided into eight subthemes, each with its own working group, which included a chair, three scientific experts, at least one community member, an IAS Research-for-Cure fellow, and an industry representative. Working groups met at least twice virtually to generate a summary of key advances and recommendations for the next five years. The steering committee consisted of the chairs of each working group, the co-chairs of the cure strategy and a community expert, selected for diversity in geographic background, gender, age, and expertise. We engaged people living with HIV at all levels as well as a wide range of scientific and nonscientific stakeholders.

The Global Cure Strategy was further refined through a broad, online stakeholder consultation, including an online survey, a review by key stakeholders in the field, and interviews with select experts and opinion leaders (more than 25 respondents). The survey received 162 responses, primarily from people working in academia, nongovernmental organizations, and hospitals or research institutions; 11% of respondents were from organizations of people living with HIV, and 4% were from industry. The majority of respondents were working in Africa, followed by Western and Central Europe, North America, and Central and South America. The summary and detailed responses can be found here: https://www.surveymonkey.com/results/SM-7YYFTZ599/.

Box 2 Key research goals to be addressed in the next 5 years

Understanding hiv reservoirs.

Define and characterize the sources of the replication- and rebound-competent viruses during ART

Define the phenotype of cells harboring intact HIV genomes

Define the clinical significance of defective yet inducible proviruses

Define the mechanisms of clonal proliferation

Determine if infected cells that persist on ART are resistant to cell death

Define the impact of sex and other factors on the reservoir and virus-specific therapies

HIV reservoir measurement

Develop and validate a high-throughput assay to quantify the rebound-competent reservoir

Develop assays that quantify integration sites

Develop assays that account for key qualitative differences in viral transcripts

Develop methods to quantify HIV protein expression in cells and tissues

Develop imaging modalities that quantify the size, distribution, and activity of the reservoir in tissues

Define the link between the cellular reservoirs, residual plasma viremia, and the rebounding virus

Develop assays for point-of-care and eventually at-home viral-load monitoring

Mechanisms of virus control

Identify the mechanisms that contribute to SIV/HIV control

Define the role of HIV-specific antibodies, B cells, and the innate immune response in virus elimination or control

Define the viral dynamics and biomarkers associated with post-treatment control

Optimize human organoid models, as well as mouse and nonhuman primate models, for cure- and remission-related studies

Targeting the provirus

Develop improved strategies to reverse latency

Develop strategies to permanently silence the provirus

Determine the impact of targeting the provirus at the time of initiation of ART

Define the role of viral subtype on the effectiveness of interventions that target the provirus

Targeting the immune system

Develop ‘reduce and control’ approaches

Develop immune modulators

Conduct clinical trials to determine whether combination immunotherapies will result in safe and durable HIV remission

Cell and gene therapy

Define the level of antigen expression needed to enable recognition of infected cells by immunotherapies

Develop gene-editing strategies that target the provirus

Develop strategies for sustained production in vivo of antiviral antibodies

Leverage advances in other biomedical fields to develop safer and more scalable approaches

Pediatric remission and cure

Characterize the establishment, persistence, and potential for preventing or reversing HIV latency in infants and children on ART

Develop assays to monitor and identify biomarkers to predict the efficacy of HIV-1 cure therapeutics

Test HIV immunotherapies and other strategies in infants and children

Social, behavioral, and ethical aspects of cure

Expand community/stakeholder engagement and capacity building

Develop HIV cure research with equity, representation, and scalability considerations

Establish standards for the safe conduct of clinical research

Integrate social, behavioral, and ethics research as part of HIV cure trials

Build capacity for basic discovery research and clinical trials in high-burden, resource-limited settings

A shared definition of the HIV reservoir is crucial for researchers, clinicians, and people living with HIV. Here, we use the term ‘HIV reservoir’ in the context of eradication or remission, as a representative term for all cells infected with replication-competent HIV in both the blood and different anatomical sites in individuals on ART—in other words, all potential sources of viral rebound in the context of a treatment interruption. Although the source of virus rebound is still not entirely understood, we now know that virus can persist in multiple forms, in multiple cells and in multiple sites.

Characterization of the complete HIV reservoir

HIV DNA can be detected in CD4 +  T cells in blood and lymphoid tissue in nearly all people with HIV on ART. These viral genomes are mainly defective. Only a small proportion (less than 5%) appear to be intact and potentially replication-competent 8 . But the HIV reservoir goes beyond circulating CD4 +  T cells; it also includes tissue-resident CD4 +  T cells and cells of the monocyte/macrophage lineage, further complicating efforts to characterize and quantify it. In vitro, HIV preferentially integrates into transcriptionally active genes 9 ; however, in people with HIV on ART, many proviruses (defined as virus that is integrated into the host genome), including intact ones, have been identified in genomic regions that are silent (known as ‘gene deserts’), which limits or precludes their reactivation 3 .

Our initial conception of the HIV reservoir as a static viral archive has given way to a more dynamic view in which, over time on ART, certain within-host HIV variants are gradually eliminated while others persist through various mechanisms, including clonal expansion of infected cells 10 , 11 , 12 , 13 , 14 , 15 . Sporadic infection of new cells during ART has been reported 16 , although there has been no convincing demonstration that viral sequences evolve during effective ART 17 , suggesting that the degree of virus spread is minimal. The sources of viral rebound following cessation of ART are incompletely defined. Multiple factors can contribute to viral replication following ART, including anatomical and microanatomical locations, the infected cell type, cellular phenotype, the nature of the provirus, the antigen specificity of the infected cell, the potential for transcriptional activity given the specific integration site, and/or distribution of antiretroviral drugs within tissues (Fig. 1 ).

figure 1

The HIV reservoir can be defined across a number of dimensions, including: (1) anatomical and microanatomical locations, (2) cell type (for example, CD4 + T cell or macrophage), (3) cell functional profile (activated or resting; resistance to killing), (4) pool of proviruses with a particular functional profile (for example, interferon-alpha resistant) or (5) triggering event (for example, response to stimulation with a particular antigen), and (6) integration-site features of the rebounding virus.

We recommend prioritizing efforts to understand integration sites of the virus during long-term ART and to understand the inducibility of a provirus on the basis of its chromosomal context. In addition, large prospective studies incorporating analytical treatment interruptions (ATIs) are still needed to probe clinically relevant sources of viral rebound and to identify a biomarker that predicts this. A favorable cure intervention could either prolong the time to the point when virus is detectable (that is, rebound) in plasma or reduce the viral ‘set point’ (that is, post-treatment control).

One of the most daunting obstacles to designing more effective methods to target persistent HIV infection is the lack of biomarkers to unambiguously identify the cells that harbor the rebound-competent reservoir. Recent work has demonstrated that the viral reservoir is preferentially enriched in cells that express programmed death-1 (PD-1) and other immune checkpoint markers, activation markers such as HLA-DR, and chemokine receptors such as CCR6 and CXCR3, but there is no phenotypic marker specific for the reservoir 18 , 19 , 20 , 21 . Specific biomarkers of the reservoir are needed, particularly to assess the impact of cure interventions. Furthermore, understanding how HIV persists in specific tissue sites and relevant local cell populations, such as those in the brain, gastrointestinal tract liver, or genital tract, will be important, given that the mechanism for persistence in each site may be distinct, and therefore different approaches may be required to eliminate each of these reservoirs.

There is growing evidence that some defective proviruses can produce transcripts and proteins (including novel viral RNAs and chimeric viral proteins) that in turn can elicit immune responses and perhaps contribute to chronic inflammation 22 , 23 , 24 , 25 . This may be of high relevance to end organ complications, such as HIV-associated neurological disease 26 . If the production of RNA and proteins from these defective proviruses proves to have clinical relevance, then their removal may be necessary to ensure long-term health.

A major mechanism of HIV persistence is the proliferation of cells that were infected prior to ART, resulting in large clonal populations of infected cells that arise as a result of the site of HIV integration 27 , 28 , response to antigen 29 , 30 , or homeostatic drivers 31 . Characterization of these presumably physiological expansions might lead to the development of therapies aimed at interrupting proliferation of infected cells. It will be important to determine to what degree these expanded clones are transcriptionally active, whether they are an important of post-ART viral rebound, and whether they have some innate survival advantage that prevents the cells from being effectively cleared by the host.

Recent studies have provided some evidence for preferential survival of infected cells with proliferative advantages or with deeper viral latency. Prosurvival and immune-resistance profiles may be particularly important in infected cells that persist despite expression of viral RNA or proteins 32 , 33 , 34 . Opportunities likely exist for collaboration and cross-fertilization of concepts with the cancer field, where the clonal dynamics of tumors have been extensively studied in relation to prosurvival and immune-resistance advantages, such as the work being done on lung cancer through prospective genetic studies in TRACRx ( https://clinicaltrials.gov/ct2/show/NCT01888601 ).

Biological sex can influence HIV pathogenesis, the immune response to HIV infection, and response to antiviral therapy 35 . Furthermore, in some but not all studies, women’s reservoirs have been shown to be less transcriptionally active and less inducible than those of men 36 , 37 , 38 , 39 , 40 . Sex, therefore, is a critical variable that should be considered as new therapies to target the reservoir are developed.

Quantification of the HIV reservoir

Significant progress toward a cure for HIV depends on having sensitive, specific, and quantitative measures of persistent virus that can be applied to various anatomical compartments 41 . Achieving this has been challenging, however, owing to the many sources and heterogeneous properties of persistent, replication-competent HIV. The reservoir can be quantified using assays that measure viral nucleic acid (total and integrated DNA, intact and defective DNA, or different forms of RNA), virus protein (p24), or viral inducibility (by measuring HIV RNA or virus replication following activation in vitro). Each approach has advantages and limitations, and assay outcomes may not always be interchangeable, comparable, or even correlated 8 .

Several groups have developed droplet digital PCR-based assays that discriminate genetically intact proviruses from a large background of defective proviruses, which are slightly less accurate but more high throughput than full genome sequencing 42 , 43 . The application of these assays to large clinical cohorts has demonstrated that there is a modest decrease in the frequency of cells with intact provirus over years on ART 44 , 45 , 46 . These assays have largely been optimized for subtype B virus, the major HIV subtype found in the United States and Europe. Yet there are over ten subtypes worldwide, some of which have evolved different mechanisms for immune evasion and persistence 47 . Pan-subtype-specific assays will need to be developed, and challenges related to cost and scalability remain. Research in this field should ideally culminate in harmonization across laboratories and crossvalidation of results. Future work will need to expand from quantification of virus in blood to quantification in tissue, particularly the more accessible tissues such as lymph nodes and gut mucosa.

Understanding the proviral landscape (defined as the degree of intactness, its transcriptional activity, and its location) is crucial, as these characteristics almost certainly influence the degree to which a provirus will rebound 48 . Over the last decade, several assays have been developed to analyze the exact location at which the virus integrates and whether the integrated virus is intact or defective. The ability to analyze single cells for integration site, viral sequence, and transcription is a major advance 48 ; however, these assays are expensive and low throughput. Technological advances are required to apply this more broadly to clinical samples, including assessment of interventions that target the reservoir.

Cell-associated viral RNA (CA-RNA) provides a measure of the total transcriptional activity of proviruses within a given sample. Several assays have recently been developed that quantify different RNA species, including total, elongated, unspliced, polyadenylated, and multi-spliced RNA, and these stand to give higher-resolution insights into the impact of therapeutic intervention 49 . An important unmet need is to develop approaches to distinguish transcripts arising from defective versus intact proviruses. Another shortcoming hampering broad use of RNA assays is the fact that they are subtype-sensitive. Overall, our ability to study the biology of transcriptionally active proviruses and the role of transcriptional activity as a potential biomarker needs to be further explored.

Since HIV protein expression is also required for recognition by HIV-specific T cells and other immune-based therapies, measuring and characterizing viral proteins in cells and tissues is an important step to understanding HIV persistence and might prove to be a critical determinant for the efficacy of therapies that target the HIV-infected cells directly (for example, chimeric antigen receptor (CAR) T cells or broadly neutralizing antibodies). Quantification of the p24 protein with ultrasensitive enzyme-linked immunosorbent assays can determine the efficacy of therapies that target the reservoir directly. Ultrasensitive p24 assays have emerged as useful tools 25 , but drawbacks include low levels of sensitivity compared with nucleic acid detection, overestimation of the replication-competent reservoir, and the requirement for specialized instrumentation 25 , 50 . Detection of viral envelope protein (the target of many therapeutic interventions for an HIV cure) also remains a challenge. Future strategies should leverage advances in single-cell techniques and new approaches to imaging tissue using super-resolution or expansion microscopy, together with multi-omics approaches.

Substantial progress in other fields of medicine has been made in using advanced imaging techniques to quantify rare diseased cells in tissues. On the basis of some preliminary success in nonhuman primate models 51 , efforts to use radiolabeled HIV-specific tracers and sensitive imaging modalities (for example, positron emission tomography, PET) have been initiated 52 . Similar efforts aimed at characterizing sites of inflammation or expression of specific surface markers that are associated with HIV persistence should also be a priority.

Several studies have attempted to identify sources of rebound virus by probing phylogenetic linkages with the proviral sequences present in various anatomical and cellular compartments. Success has been limited, however, in part owing to the challenging nature of obtaining full-length sequences from the limited number of infected cells in blood or tissue, as well as from plasma with low level viremia 53 . Strategies that can enhance enrichment of infected cells and/or depth of viral sequencing together with high-throughput low-cost single-cell analyses are likely to advance the field. As the RNA in circulating virions is a well-accepted surrogate marker for untreated HIV disease, this measurement could be an effective tool to characterize the rebound-competent population of HIV-infected cells.

Currently, any impact of a therapeutic intervention on the viral reservoir can only be determined with an ATI. A tool for very early detection of viral rebound post-ART using a nonvirological marker—such as measures of the innate immune response 54 —could be very valuable. In addition, better ways to monitor viral load that do not require frequent healthcare appointments will be needed 5 . This should include the development of home-based tests that may not necessarily require high sensitivity as long as testing is performed frequently 55 . Finally, emerging evidence suggests that virus replication during an ATI may be associated with some long-term adverse events 56 , so careful follow up of participants in ATI studies will be necessary.

Mechanisms and models of virus control

Natural control in people living with hiv.

Individuals who naturally control HIV in the absence of any therapy and can maintain a viral load of <50 copies/ml (known as ‘elite’ controllers) have been the focus of intense investigation for years. Research in this area is increasingly focused on those controllers who exhibit remarkably stringent control (‘exceptional’ controllers) 57 , 58 , some of whom might be considered true cures 48 , 59 , and those who became controllers after ART interruption (post-treatment controllers) 60 , 61 . In exceptional controllers, the frequency of infected cells is extremely low, often below the limit of detection of most standard assays for HIV DNA 57 , 59 , there is no intact virus 48 and the site of HIV integration may be distinct 48 ; an agreed definition for an exceptional controller is needed.

Virus-specific CD8 +  T cells targeting particularly vulnerable or conserved epitopes are generally recognized as the key mediator of elite control; such cells are rare in post-treatment controllers and have not yet been characterized in exceptional controllers 4 , 62 . Further characterization of the various controller phenotypes (elite, exceptional, post-treatment) should remain a priority; the identification of unique and potentially informative phenotypes should also be pursued, including individuals on ART who have very small reservoirs 62 . Functional multi-omics studies and emerging single-cell technologies should help to determine the mechanisms involved in exceptional, elite, and post-treatment control. Better animal models of exceptional and post-treatment control would greatly enhance the field, giving access to tissue and the opportunity for longitudinal assessment of virus control 63 .

Virus elimination and control will likely require a coordinated immune response involving more than just T cells. Recent data suggest that autologous antibodies targeting archived viruses as well as interferon sensitivity might influence which virus populations emerge post-ART 54 , 64 , 65 . Studies in simian immunodeficiency virus (SIV)-infected nonhuman primates that naturally control infection have provided indirect evidence that natural killer (NK) cells might be able to effectively control virus in tissues 66 . Better insights into the role of antibodies, natural killer cells, and innate immunity in post-treatment and/or post-intervention control are needed.

The interplay between the virus and immune system during acute infection or immediately after the interruption of ART is largely unknown, at least in humans. During acute infection, those destined to become controllers typically have an initial period of poorly controlled viremia 61 , 67 . For post-treatment controllers, virus control is often achieved more rapidly after cessation of ART than after primary infection 61 , 68 . We need to understand the viral dynamics associated with eventual post-ART control/remission, as this will inform how a treatment interruption should be conducted. It is likely that biomarkers other than the plasma HIV RNA level might allow for the development of safer and more cost-effective strategies for interrupting ART.

Animal models of control

The role of humanized mouse models in cure research is still evolving. Recent studies showing similar effects of latency-reversing strategies in mice and the less scalable nonhuman primate model are encouraging 69 , 70 . Given that access to nonhuman primates for cure studies will likely remain a barrier, ongoing optimization, standardization, and validation of mouse models should be prioritized.

An important discrepancy in translating cure-related findings from SIV-infected nonhuman primates to people with HIV lies in the duration of ART. Although effective ART regimens with integrase inhibitors have been optimized in nonhuman primates, high costs, and treatment-related toxicities necessitate relatively shorter study durations (less than 1–2 years of ART). One possible solution would be for primate research centers to maintain colonies of SIV-infected nonhuman primates receiving very-long-term ART to be directly assigned for studies.

There is ongoing debate about the most appropriate virus to be used in cure-related studies in nonhuman primates. Investigations utilizing broadly neutralizing antibodies or select vaccines directed against the HIV-1 envelope necessitate infection with a virus that expresses HIV envelope proteins (simian-human immunodeficiency virus, SHIV). However, SHIV infections with some strains are characterized by post-treatment control in the absence of any intervention 71 , while others can induce significant disease progression 72 . Therefore, the specific strain used can limit the generalizability of the model. Although SIV infection of nonhuman primates can cause more significant disease progression than HIV infection of people, early ART for SIV infection can limit rapid disease progression and is therefore a useful model for cure studies 73 . Developing immunotherapies that target the SIV envelope in addition to SHIV should also be pursued.

A major recent advance has been the development of genetically barcoded SIV mac239 strains 74 . Because the barcode ‘tags’ are easily quantified and also passed on to progeny virus, this model allows for tracking of clonal dynamics, providing more precise insights into how interventions affect seeding of the reservoir, viral reactivation during ART, or viral recrudescence after ART interruption.

Therapeutic interventions

Since the discovery that HIV can establish a latent infection with minimal HIV transcription, a range of approaches has emerged that specifically target latently infected cells. These include pharmacological modulation of epigenetic or signaling pathways involved in HIV transcription to reactivate latent HIV such that the cells can be targeted and eliminated (‘shock and kill’) or to permanently silence HIV transcription (‘block and lock’) 75 , 76 , 77 . Recent reports have demonstrated that HIV latency is heterogeneous and that latency reactivation is stochastic, implying that a combination of agents targeting various pathways controlling HIV transcription may be necessary to achieve either robust silencing or latency reversal 49 , 78 , 79 , 80 .

A clear limitation of the ‘shock and kill’ approach comes from the discovery that only a fraction of proviruses is intact and among these, only some are inducible by a potent stimulus such as T cell stimulation, let alone by far less potent latency-reversing agents (LRAs) 8 , 81 , 82 , 83 . Furthermore, cells containing reactivated latent HIV may also be relatively resistant to killing by cytotoxic T cells 84 . Complicating the situation even more, CD8 +  T cells appear to suppress HIV transcription and can blunt the effect of LRAs 70 .

Although LRAs tested in humans can induce HIV RNA expression and virion production in vivo, they have failed to reduce the size of the reservoir, even when combined with immunotherapeutic strategies designed to enhance clearance of infected cells 85 , 86 , 87 , 88 , 89 , 90 . This could be due to poor antigen induction by LRAs or insufficient clearance of these targets by immunotherapies (Fig. 2 ). Furthermore, many of the tested LRAs have off-target effects. Newer approaches for delivery of LRAs to reduce toxicity, enhance potency, and improve targeting, potentially leveraging advances in nanomedicine, should be explored. Greater potency could potentially be achieved using LRAs in combination, however, care is needed in these clinical trials, given that unexpected toxicities can emerge—as was recently demonstrated in the evaluation of high-dose disulfiram and vorinostat 91 . Finally, LRAs will likely need to be partnered with therapies that enhance the clearance of cells expressing viral proteins, such as immune-enhancing strategies or proapoptotic drugs 92 .

figure 2

Reversing latency is an important component of revealing HIV-infected cells, allowing for conversion of a latently infected to a productively infected cell. a , Currently available LRAs reverse latency in only a subset of infected cells, and, when used alone, do not sufficiently eliminate these. b , Enhancing the efficacy of an LRA can be achieved with increased potency, targeted delivery or through using combinations of LRAs. c , Ultimately, depletion of the reservoir will require combining an LRA with other interventions, such as immunotherapy or a proapoptotic drug.

Permanently silencing the HIV promoter by suppressing factors that promote HIV transcription has also emerged as a strategy to target the provirus. The concept is to therapeutically drive HIV into a permanently silenced epigenetic state that resists reactivation (‘deep latency’). The Tat inhibitor didehydro-cortistatin A (dCA) blocks HIV reactivation from human CD4 +  T cells in vitro through epigenetic repression; treatment with dCA in ART-suppressed humanized mouse latency models induces a measurable delay in virus rebound 76 , 93 . Gene therapy can also play an important part in permanent silencing of the provirus using short interfering RNA or other modalities 94 . Thus far, these approaches have yet to be successfully translated into human trials.

Further exploration of the therapeutic potential of permanently silencing the reservoir (‘block and lock’), presumably as part of a combinatorial cure approach, is a high research priority. Some pathways that might be targeted include mTOR, HSF1, and others 95 , 96 , 97 . Efforts to screen for drugs that suppress HIV transcription are encouraged, 96 , 98 , 99 with the goal to rapidly move into preclinical and clinical studies 100 , 101 .

With a recent report indicating that the HIV reservoir is stabilized at the start of ART initiation, efforts should be devised to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART, where such interventions are ideally delivered at ART initiation 102 , 103 , 104 .

Most methods to target the provirus have been developed using subtype B. Thus, while conserved mechanisms govern latency across the different virus subtypes, differences at the level of the promoter may impact responsiveness to various stimuli. Therapies targeting the provirus should be evaluated across multiple HIV subtypes including recombinants.

There is a robust and growing toolbox of immune therapies that might be advanced to proof-of-concept testing. Arguably, the most impactful innovation to date is the isolation and development of broadly neutralizing antibodies for clinical use, but advances have also been made in the development of therapeutic vaccines, vaccine adjuvants, and other immunotherapies. When used in combination in nonhuman primates, these immune therapies have resulted in sustained post-ART control 71 , 105 . When used alone, most of these approaches have had limited effectiveness in people, although some promising results are emerging 88 , 106 , 107 . Combination clinical trials have recently started and are ongoing. Although the combination of either vorinostat or romidepsin (HDAC inhibitors that can increase viral transcription through epigenetic modification) together with different HIV vaccines showed no or minimal reduction in the HIV reservoir 107 , 108 , 109 , results from other studies including a combination of Toll-like receptor agonists, LRAs and broadly neutralizing antibodies are eagerly awaited ( NCT03837756 ; NCT04319367 ; NCT03041012 ).

As it may be challenging to reactivate and eliminate all latently infected cells, or to induce deep irreversible latency in all cells, it seems unlikely that these approaches will be curative by themselves. By reducing the reservoir, however, they might make strategies aimed at controlling the virus long term post-ART more effective. This overall approach of 'reduce and control’ is supported by observations in elite and post-treatment controllers, and theoretical modeling 110 . Multiple approaches that might result in control of a small reservoir are being developed. Assessment of therapeutic vaccines including live vector vaccines such as adenovirus 26, modified vaccine Ankara, and also a cytomegalovirus in nonhuman primate models have been particularly promising, with a subset of animals achieving eradication of virus 71 , 111 . Such studies have not yet been performed in people. Research to develop and test novel immunogen and vaccine designs with broad, potent and durable immunity should be prioritized. Given the recognition that autologous neutralizing antibodies might contribute to reservoir control 64 , novel vaccine approaches aimed at the induction of broadly neutralizing antibodies—including germline targeting 112 —should also be prioritized.

Immune stimulators, immunomodulators, and novel immunotherapies (such as cytokine formulations, Toll-like receptor agonists, immune checkpoint inhibitors or agonists, and novel vaccine adjuvants), used alone or more likely in combination with other approaches, hold promise but have undergone relatively limited testing in HIV-cure studies in people so far 106 , 113 , 114 , 115 .

With the exception of a few anecdotal cases 116 , immunotherapy in people with HIV has yet to recapitulate the promising advances made in nonhuman primates. Combination of various therapies will almost certainly be needed (Fig. 3 ). Conducting such studies is feasible 108 , 117 ; it is expected that initial clinical research will be intensive in nature and designed to identify strategies that might then be tested in well-powered, controlled clinical trials. Defining the mechanisms and potential biomarkers associated with remissions/cures in the preclinical and clinical setting should remain a priority. Determining which combinations to study, and how to define the optimal doses and strategies, poses a significant challenge from a methodological and regulatory perspective. As immunotherapies for HIV move into the clinic, careful attention will have to be paid to immune-related adverse events, including cytokine-release syndrome and autoimmunity.

figure 3

Strategies that will enhance immune-mediated clearance of latently infected cells include early initiation of ART and the administration of combined interventions at the time of suppressive ART (colored arrows) or during the treatment interruption phase, which will allow for increased antigen presentation. Given that there is no biomarker that can predict viral rebound, analytical treatment interruptions are used to determine whether the intervention has had a clinically meaningful impact. The overarching goal is to either delay viral rebound by at least months or years or reduce the set point of virus replication (that is, the stable level of viral load that the body settles at), preferably to a level of <200 copies/ml. The dashed colored lines represent different potential favorable outcomes from a cure intervention. bNAbs, broadly neutralizing antibodies; LRA, latency reversing agent; TLR, Toll-like receptor.

Cell and gene therapy clinical trials for people with HIV, although safe so far, have been small in scale and with no clear demonstrations of efficacy. The interest in gene therapy for an HIV cure was inspired by the elimination of intact virus in Timothy Brown (also known as the Berlin patient) and Adam Casteljo (also known as the London patient), who both received stem-cell transplants from a CCR5-negative donor 1 , 2 to treat their underlying malignancies. CCR5 is a co-receptor that is needed by most strains of HIV to enter a cell; a reduction in the size of the reservoir has also been reported following stem-cell transplantation to people with HIV from donors who are CCR5-positive 118 , 119 , but the HIV reservoir can’t be completely eliminated, irrespective of the CCR5 status of the donor. In the case of CCR5-negative stem-cell transplantation, the absence of CCR5 in the donor cells is thought to protect the newly transplanted cells from infection, at least with CCR5-dependent HIV strains. Interestingly, in both cases of cure following stem-cell transplantation of CCR5-negative cells, defective virus has been detected, but not intact or replication-competent virus 120 , 121 . These reports have prompted researchers to evaluate CCR5-targeted gene editing as a potentially safer path to cure in people living with HIV on ART, given the high mortality rate and significant morbidity associated with stem-cell transplantation. Timothy Brown unfortunately died in early 2020 owing to recurrence of his leukemia, but remained HIV-free until his death.

Ex vivo gene editing of CCR5 using zinc finger nucleases and re-infusion of CCR5-modified T cells has not yet prevented viral rebound following ATI 122 , 123 , possibly because insufficient cell numbers were engineered and/or engrafted with first-generation editing tools and cell culture protocols and/or because CCR5 disruption alone cannot shift the balance in favor of post-treatment control in the presence of persistently infected cells. More recently, gene therapies have shifted to creating effectors, including chimeric antigen receptor (CAR) T cells, which can recognize and eliminate HIV-infected cells (Fig. 4 ). Other approaches include the use of novel delivery systems to deliver genes to local tissues, resulting in the sustained production of systemically acting antivirals such as broadly neutralizing antibodies 124 , 125 and CD4 mimetics 126 . Finally, attempts are being made to directly target integrated proviruses with technologies such as CRISPR–Cas9 and recombinases 127 , 128 . This approach remains conceptually challenging in view of the disparate locations of latently infected cells, the absence of specific markers to target delivery, the heterogeneity of proviral sequences (the majority of which are defective), and the risk of off-target effects.

figure 4

Examples of ex vivo (left) and in vivo (right) gene therapy approaches that have been tested in people with HIV on ART. Ex vivo strategies include gene editing to either delete or inactivate CCR5 or HIV provirus in CD4 + -enriched T cells using gene-editing tools such as zinc finger nucelases (ZFN) or CRISPR–Cas9. Alternatively, autologous T cells can be modified to express a CAR that can recognize HIV envelope, and this can then be reinfused into the participant. In vivo strategies, on the other hand, do not require external manipulation of cells; nanoparticles or viral vectors (such as adeno-associated virus (AAV)), which encapsulate mRNA or DNA, respectively, for the relevant gene to be expressed are administered directly to the patient. These approaches have recently been successful using lipid nanoparticles that contain mRNA encoding CRISPR–Cas9 135 or for expression of anti-HIV broadly neutralizing antibodies such as PG9 or VRC07 (ref. 125 ). PBMCs, peripheral blood mononuclear cells; PLWH, person living with HIV.

Many emerging cell and gene therapies are designed to target viral proteins/epitopes that are expressed in abundance on the surface of tumor cells, for example CD19 for the treatment of lymphoma 129 . Various forms of the HIV viral envelope protein (gp120 trimers and monomers, gp41) are expressed on the surface of infected cells, while multiple peptides are presented via HLA molecules. These antigens are expressed at levels well below that of many cancer antigens now being successfully targeted in the clinic. Cell-based therapies such as CAR T cells, once infused into the patient, will only persist and differentiate if there is sufficient antigenic exposure; however, the levels of antigen during ART may be too low 130 . Removal of ART after infusion of CAR T cells (or similar products) could be used to expand these cells in vivo, or more potent latency-reversing agents could be used to enhance envelope protein expression. In addition, novel adjuvants could expand CAR T cells even when the antigen burden is low, as was recently demonstrated in the nonhuman primate model 131 .

The challenges here are primarily those of delivery to relevant cells. In addition to developing methods to target specific cells, which are common problems faced by all potential in vivo gene therapies, targeting latent proviruses also presents the problem of a lack of robust cell surface markers to identify cells harboring such proviruses. Progress in both of these areas will be needed to develop strategies to deliver gene-editing reagents to latently infected cells. Some promising in vivo delivery strategies for CRISPR–Cas9 have included adeno-associated virus to target the SIV virus in nonhuman primates on ART 127 , as well as using engineered CD4 +  cell-homing messenger RNA (mRNA)-containing lipid nanoparticles in mouse models of HIV infection 132 .

Long-term in vivo secretion of antibodies or antibody-like molecules can be achieved following gene therapy vector delivery of antibody cassettes to tissues such as muscle and liver, where enhanced production of antibodies is needed, rather than specific delivery to infected CD4 +  T cells. This can be achieved through direct intramuscular injection leading to uptake in the muscle or, alternatively, intravenous injection, which will allow for uptake in the liver. Ectopic expression of these antibodies in liver or muscle cells fails to recapitulate aspects of natural antibody production, such as responsiveness to antigen and ongoing somatic hypermutation. Therefore, editing the B cell Ig locus itself to express antibodies presents an alternative and attractive gene-editing strategy 133 , 134 .

Sustained production of these antivirals could result in sustained (perhaps lifelong) control of the virus. Many barriers to success exist. Antidrug antibodies that target and clear the vectors often form rapidly 125 , limiting the ability to deliver multiple doses. Advances in mRNA encapsulation within lipid nanoparticles may potentially revolutionize delivery of gene therapy, allowing for delivery of mRNA encoding CRISPR–Cas9 and related guide RNAs in vivo, as has recently been successfully demonstrated in the treatment of transthyretin amyloidosis 135 . Also, antibodies targeting multiple antigens will likely need to be produced at high levels to prevent virus replication and escape.

Advances in T cell manufacturing are expected, driven by cancer CAR T cell therapies, which will also benefit HIV therapies. Similarly, advances occurring in gene therapy treatments for genetic diseases, such as hemoglobinopathies, are catalyzing safer and nongenotoxic conditioning for HSPC transplants, for example based on drug–antibody conjugates. Practicality will also be enhanced by moving toward using allogeneic off-the-shelf products.

Gene and cell therapies now require a shift towards a practical focus, identifying ways to expand use, reduce costs, and allow deployment in resource-limited settings. This could be achieved through abbreviated ex vivo cell manufacturing, including automated closed-system devices (‘gene therapy in a box’), to produce product in a place-of-care setting 136 . While still in the early stages of development, in vivo gene therapy also presents exciting possibilities to significantly expand access by eliminating the need for external manipulation of cells and associated technological requirements.

The unique context of perinatal HIV infection necessitates pediatric-specific strategies to achieve ART-free remission in children. The case of the Mississippi child, who started therapy ~30 hours after birth and achieved remission off ART for 27 months before virus rebounded 137 , 138 , raised the possibility that remission for children can be attained. Subsequent reports of early-treated pediatric cases with long-term (>12 years) virological control off ART have provided examples of post-treatment control in children 139 , 140 .

The nature of the reservoir in children is unique from that in adults. For example, naive CD4 +  T cells are a more important reservoir for the virus in children 141 , 142 . Further development of infant nonhuman primate models for evaluating ART and cure strategies will contribute to our understanding of the HIV reservoir and how to target it in the unique setting of infancy and immune development, but an understanding of the limitations of this model is also crucially important 141 , 142 , 143 , 144 , 145 .

Many of the recent advances in understanding HIV persistence during ART in adults, including frequency and transcriptional activity of intact virus, clonal expansion, sites of proviral integration, and inducibility, need to be applied to studies of children. Optimizing methods that can be adapted to small blood volumes are also needed.

In the context of childhood infection, clarity is needed on how latency is established in naive T cells, susceptibility of these cells to latency reversal, propensity for T cells to clonally expand, and the relative contribution of clonally expanded cells to viral rebound following cessation of ART. It is still unclear whether integration sites and reactivation potential are different in children, and whether these change with age. Given that initial studies suggest a less-inducible reservoir in cases of perinatal infection 146 , it is especially important to determine how to maximize latency reversal in children. The optimal timing of these interventions (for example, at the time of early ART initiation) could potentially limit the pool of infected cells that persist on ART; such approaches can be explored in a nonhuman primate model.

As in adults, better tools are needed to assess the impact of cure interventions in children, including quantification of HIV persistence and in-depth cellular immune profiling. There is a particular need for noninvasive tools, such as total body imaging, to assess central nervous system and other tissue-based reservoirs. It will also be important to identify biomarkers for post-treatment control, including the degree of reduction or alteration in the composition of the latent reservoir that may be predictive of pediatric remission or cure 147 . Finally, preclinical studies in infant nonhuman primates that test new interventions to reduce or eliminate persistent HIV and/or induce viral remission after ART interruption are needed to inform the development of HIV remission and cure intervention strategies. Early therapy alone is insufficient to reliably achieve a cure or long-term remission in children. Novel approaches, including earlier administration and use of more potent antiretroviral drugs, therapeutic vaccines, or other immunotherapeutics, such as broadly neutralizing antibodies and/or innate-immune-enhancing agents, will be necessary.

Research directed toward an HIV cure intertwines critical social, behavioral, and ethical aspects that must be incorporated in the scientific agenda. This research takes place within particular social contexts and communities that shape its permissibility and appropriateness. Accordingly, affected communities must be meaningfully engaged throughout the research process; social and behavioral factors must be interrogated and taken into account because they affect research feasibility, community support for the research, and the well-being of participants and other stakeholders. Research must also address the many ethical issues associated with developing a therapy, particularly since viable options for treatment are already available. Sufficient funding for research toward social, behavioral, and ethical aspects of a cure and for community involvement is therefore essential.

Substantial progress using more conceptual and normative approaches has also been made regarding the ethical issues associated with the interruption of ART 148 , 149 . Similarly, there has been attention focused on acceptable risk thresholds for research 150 . Finally, given the important role of treatment as prevention, efforts have focused on the ethics of partner-protection measures 151 .

Community engagement in HIV cure research is still suboptimal in many settings, being mostly been limited to advisory boards typically comprised of scientifically literate individuals. Capacity to discuss HIV cure research and to evaluate its potential implications for local and global communities must be built within diverse community groups. Communities should be empowered and supported through education and engagement at all levels of the research process to help shape the HIV cure research agenda and allow for potential study participants to have a voice in trial design 152 .

Since HIV cure research is highly complex and nuanced, there is also a need to ensure understanding of it among other key stakeholders, including Institutional Review Boards (IRBs) and clinicians. For example, IRBs need to appreciate the implications of ATIs for partners who they may not see as within their remit, and clinicians need to understand the rationale for ATIs in the research setting.

Attention must focus on broad representation (for example, age, race and ethnicity, gender and sexuality, geographic location, risk behaviors) in research. Diversity in participation is essential during the development of interventions aimed at complete HIV elimination or durable ART-free control. This necessitates research directed at understanding the reasons for under-representation of certain groups of people in HIV cure research. For example, cisgender and transgender women, as well as individuals of some racial and ethnic backgrounds, are less likely to participate in HIV-cure-focused clinical trials 153 . This highlights the need for more nuanced and theoretically engaged research to understand how gender, race, and other characteristics shape engagement with HIV cure research 154 . At the same time, legal and social considerations unique to each context must be identified and addressed. For example, local laws, stigma, and access to healthcare affect research involving the interruption of ART.

There is also a need to better define ethical considerations involved in the selection of populations of interest in which promising cure strategies will be tested. For example, should priority be given to testing new interventions in individuals who initiated treatment during acute infection over those who began treatment during chronic infection? What are the best means to identify and manage the ethical considerations in pediatric HIV cure research? In addition, what measures ought to be taken to ensure that recruitment is not skewed toward people with HIV in resource-limited settings? Further, ethical questions of equity and justice related to the distribution of safe and effective cure interventions must consider acceptability, scalability, and cost-effectiveness. The COVID-19 pandemic has raised unique considerations for research participants, staff, and communities 155 . Given the rapidly changing nature of the pandemic and the availability of COVID-19 vaccines and other treatments, there is a need to continually revise and assess the safety and feasibility of HIV cure research efforts.

During the study design phase, early engagement is needed in communities where research is being considered in order to determine the nature and acceptability of research-related risks. Similarly, stakeholder perceptions should be elicited to guide the development of target product profiles (the minimal and optimal characteristics of a new therapeutic intervention), as recently done for an HIV cure 5 . In especially complex clinical studies, formative research should be used to help develop a robust, informed consent process. Furthermore, nested social and behavioral research (basic, elemental, supportive, integrative) is needed to enhance understanding of the actual experiences of trial participants as well as of sexual partners of participants. These data will help provide a check on current practices, as well as provide a foundation for future efforts aimed at improving them.

Several of the key topics addressed in the previous sections are prerequisites for the development of successful cure strategies and interventions. To date, most HIV cure research has been restricted to high-income countries with relatively low HIV burden and has most often engaged men who have sex with men. HIV strains are genetically and biologically diverse, and host mechanisms of antiviral immunity required for durable control may differ by sex, geography, and ethnicity. Basic discovery research and clinical trials in resource-limited settings must be strengthened and will require enabling infrastructure development and capacity building.

In the next decade, we expect to see a greater understanding of HIV reservoirs, an increasing number of clinical trials and hopefully reports of individuals who achieved long-term remission with less intensive and more widely applicable strategies. On the basis of the current understanding and lessons from ART, it is likely that combinations of these approaches may be the first approach to be implemented. Inclusion of knowledge from fields such as oncology and COVID-19 could also greatly facilitate progress. Finally, open and responsible communication about trials and realistic expectations will remain important. Although safety is the highest priority, with increasing number of clinical trials, there is an increase in the possibility of adverse events which will need to be appropriately managed while allowing the field to advance.

This global scientific strategy, in combination with the recently developed target product profile 5 , will assist with guiding the field toward a widely applicable, acceptable, and affordable cure. The establishment of the HIV Cure Africa Acceleration Partnership 152 will hopefully enable broader engagement and facilitate rapid implementation of any successes into low- and middle-income settings. Fortunately, the resources for such work remain available, and the field is highly committed to making the long-term commitments necessary to develop an effective and scalable remission or cure strategy.

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Acknowledgements

We acknowledge the generous contribution of all the participants in the working groups, the key opinion leaders who read and provided feedback on the strategy, participants in the online survey and secretarial support from the International AIDS Society. S.R.L. and S.G.D. are funded by National Institutes of Health Delaney AIDS Research Enterprise (DARE) Collaboratory (UM1AI126611 and UM1AI164560). S.R.L. is also funded by the National Health and Medical Research Council (NHMRC; grant number GNT1149990) of Australia and the Australian Centre for HIV and Hepatitis. R.B.J. is funded by the NIH UM1AI64565. C.T.T. is funded by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (grant 84177). O.L. is funded by the ANRS, Sidaction, University Paris Saclay, Inserm, and CEA (Commissariat à l’Energie Atomique). P.C. is funded by the NIH (HL156247 and AI164561); N.A. is funded by the NIH Delaney CARE Collaboratory 1UM1AI126619 and from R01AI134363; T.N. is funded by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (grant 64809), The Bill and Melinda Gates Foundation (INV-033558), the International AIDS Vaccine Initiative (UKZNRSA1001) and DFG German-African Network grant (grant number AL 1043/6-1).

Author information

Authors and affiliations.

University of California San Francisco, San Fransisco, CA, USA

Steven G. Deeks & Steven Deeks

UNC HIV Cure Center, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

  • Nancie Archin

University of Southern California, Los Angeles, CA, USA

  • Paula Cannon

HIV i-Base, London, UK

Simon Collins

Weill Cornell Medicine, Cornell University, New York, NY, USA

  • R. Brad Jones

Aidsfonds, Amsterdam, the Netherlands

Marein A. W. P. de Jong & Marein de Jong

University Paris Saclay, AP-HP, Bicêtre Hospital, UMR1184 INSERM CEA, Le Kremlin Bicêtre, Paris, France

  • Olivier Lambotte

International AIDS Society, Geneva, Switzerland

Rosanne Lamplough

Africa Health Research Institute and University of KwaZulu-Natal, Durban, South Africa

  • Thumbi Ndung’u

University College London, London, UK

Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA

Thumbi Ndung’u & Krista Dong

Berman Institute of Bioethics and Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

  • Jeremy Sugarman

National Institute for Communicable Diseases and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

  • Caroline T. Tiemessen

UZ Ghent, Ghent, Belgium

  • Linos Vandekerckhove

Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

Sharon R. Lewin

Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia

Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

Sharon R. Lewin & Sharon Lewin

UKZN, Durban, South Africa

Zaza Ndhlovu

Centre de Recherche du CHUM and Université de Montréal, Montreal, Canada

Nicolas Chomont

BC Centre for Excellence in HIV/AIDS, Faculty of Health Sciences, Simon Fraser University, Vancouver, Canada

Zabrina Brumme

Sun Yat-sen University, Guangzhou, China

ViiV Healthcare, Branford, CT, USA

Luke Jasenosky

Treatment Action Group, New York, NY, USA

Richard Jefferys

Institut Pasteur, Université de Paris, Unité HIV, Inflammation et Persistance, Paris, France

Aurelio Orta-Resendiz

National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA

Frank Mardarelli

UMC Utrecht, Utrecht, the Netherlands

Monique Nijhuis

Perelmann School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Katharine Bar & Pablo Tebas

Merck & Co., Inc., Department of Infectious Disease & Vaccines, Kenilworth, NJ, USA

Bonnie Howell

European AIDS treatment group (EATG), Zurich, Switzerland

Alex Schneider

1CONICET – Universidad de Buenos Aires. Instituto de Investigaciones, Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina

Gabriela Turk

Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina

Makerere University, Makerere, Uganda

Rose Nabatanzi

John Hopkins School of Medicine, Baltimore, MD, USA

Joel Blankson

ICATS, UNC School of Medicine, Chapel Hill, NC, USA

J. Victor Garcia

Emory University School of Medicine, Yerkes National Primate Research Center, Atlanta, GA, USA

Mirko Paiardini

ViiV Healthcare, London, UK

Jan van Lunzen

Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

Christina Antoniadi

Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil

Fernanda Heloise Côrtes

Scripps Research Institute, Jupiter, FL, USA

Susana Valente

Aarhus University Hospital, Aarhus, Denmark

Ole S. Søgaard

Universidade Federal de Sao Paulo, Sao Paulo, Brazil

Ricardo Sobhie Diaz

Gladstone Institute of Virology, University of California San Francisco, San Francisco, CA, USA

Melannie Ott

USAHIV Drug Discovery, ViiV Healthcare, Qura Therapeutics, and UNC HIV Cure Center, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA

Richard (Rick) Dunham

EATG, Berlin, Germany

Siegfried Schwarze

Queen’s University, Kingston, Ontario, Canada

Santiago Perez Patrigeon

MUJHU Care limited, Kampala, Uganda

Josephine Nabukenya

The Rockefeller University, New York, NY, USA

Marina Caskey

IrsiCaixa AIDS Research Institute, HUGTIP, Badalona, Barcelona, Spain

Beatriz Mothe

Chinese Academy of Sciences, National Clinical Research Center for Infectious Diseases, Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, Beijing, China

Fu Sheng Wang

Imperial College London, Department of Infectious Disease, Faculty of Medicine, London, UK

Sarah Fidler

Gilead Sciences, Foster City, CA, USA

Devi SenGupta

European AIDS Treatment Group (EATG), Brussels, Belgium

Stephan Dressler

University of North Carolina Project Malawi, Lilongwe, Malawi

Mitch Matoga

Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Hans-Peter Kiem

Joint Clinical Research Centre, Kampala, Uganda

Cissy Kityo

Caring Cross, Gaithersburg, MD, USA

Boro Dropulic

University of Washington, Seattle, WA, USA

Michael Louella

Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia

Kumitaa Theva Das

Johns Hopkins University School of Medicine, Baltimore, MD, USA

Deborah Persaud

Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA

Ann Chahroudi

University of Massachusetts, Worcester, MA, USA

Katherine Luzuriaga

Chulalongkorn University, Bangkok, Thailand

Thanyawee Puthanakit

ImmunityBio, Inc, Culver City, CA, USA

Jeffrey Safrit

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana

Gaerolwe Masheto

UNC Gillings School of Global Public Health, Chapel Hill, NC, USA

Karine Dubé

La Trobe University, Melbourne, Australia

Jennifer Power

AVAC, New York, NY, USA

Jessica Salzwedel

VARG, Chiang Mai, Thailand

Udom Likhitwonnawut

UCSD AntiViral Research Center, Delaney AIDS Research Enterprise/UCSF, Palm Springs, CA, USA

Jeff Taylor

Social Policy, Gender Identity, and Sexual Orientation Studies Association (SPoD), University of Lucerne MSc Health Sciences, Istanbul, Turkey

Oguzhan Latif Nuh

Rakai Health Sciences Program, Rakai, Uganda

Edward Nelson Kankaka

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Core Leadership Group

  • Steven Deeks
  • , Sharon Lewin
  • , Marein de Jong
  • , Rosanne Lamplough
  •  & Simon Collins

Working Group 1 (Understanding HIV reservoirs)

  • , Zaza Ndhlovu
  • , Nicolas Chomont
  • , Zabrina Brumme
  • , Luke Jasenosky
  • , Richard Jefferys
  •  & Aurelio Orta-Resendiz

Working Group 2 (HIV reservoir measurement)

  • , Frank Mardarelli
  • , Monique Nijhuis
  • , Katharine Bar
  • , Bonnie Howell
  • , Alex Schneider
  • , Gabriela Turk
  •  & Rose Nabatanzi

Working Group 3 (Mechanisms of virus control)

  • , Joel Blankson
  • , J. Victor Garcia
  • , Mirko Paiardini
  • , Jan van Lunzen
  • , Christina Antoniadi
  •  & Fernanda Heloise Côrtes

Working Group 4 (Targeting the provirus)

  • , Susana Valente
  • , Ole S. Søgaard
  • , Ricardo Sobhie Diaz
  • , Melannie Ott
  • , Richard (Rick) Dunham
  • , Siegfried Schwarze
  • , Santiago Perez Patrigeon
  •  & Josephine Nabukenya

Working Group 5 (Targeting the immune system)

  • , Marina Caskey
  • , Beatriz Mothe
  • , Fu Sheng Wang
  • , Sarah Fidler
  • , Devi SenGupta
  • , Stephan Dressler
  •  & Mitch Matoga

Working Group 6 (Cell and gene therapy)

  • , Hans-Peter Kiem
  • , Pablo Tebas
  • , Cissy Kityo
  • , Boro Dropulic
  • , Michael Louella
  •  & Kumitaa Theva Das

Working Group 7 (Paediatric remission and cure)

  • , Deborah Persaud
  • , Ann Chahroudi
  • , Katherine Luzuriaga
  • , Thanyawee Puthanakit
  • , Jeffrey Safrit
  •  & Gaerolwe Masheto

Working Group 8: (Social, behavioral and ethical aspects of cure)

  • , Karine Dubé
  • , Jennifer Power
  • , Jessica Salzwedel
  • , Udom Likhitwonnawut
  • , Jeff Taylor
  • , Oguzhan Latif Nuh
  • , Krista Dong
  •  & Edward Nelson Kankaka

Contributions

S.G.D., S.R.L., M.D.J. and R.L. developed the method for generating the strategy and oversaw the governance and establishment of the working groups. All authors on the masthead were members of the steering group. All authors of the IAS Global Scientific Strategy writing group contributed to the writing and approved the submitted version of the manuscript. Members of the IAS Global Scientific Strategy working groups are identified in the list at the end of the manuscript.

Corresponding authors

Correspondence to Steven G. Deeks or Sharon R. Lewin .

Ethics declarations

Competing interests.

S.G.D. receives research support from Gilead and Merck. He is a member of the scientific advisory boards for BryoLogyx, Enochian Biosciences and Tendel. He has consulted for AbbVie, Biotron, Eli Lilly, GSK/ViiV and Immunocore; J.S. is a member of Merck KGaA’s Ethics Advisory Panel and Stem Cell Research Oversight Committee; a member of IQVIA’s Ethics Advisory Panel; a member of Aspen Neurosciences Clinical Advisory Panel; a member of a Merck Data Monitoring Committee; a consultant to Biogen; and a consultant to Portola Pharmaceuticals Inc. None of these activities are related to the issues discussed in this manuscript; T.N. has received research funding from Gilead Sciences; O.L. has been paid expert testimony and consultancy fees from BMS France, MSD, Astra Zeneca; consultancy fees from Incyte, Sobi, grants from ViiV and Gilead; L.V. receives research grants from J&J, ViiV Healthcare and Gilead Sciences; P.C. is a member of Gilead’s HIV Cure Advisory Board; S.R.L.’s institution receives funding for investigator initiated research from Gilead, Merck and Viiv. She has research collaborations with BMS, Abbvie and Merck. She has received honoraria paid to her for membership of advisory boards to Gilead, Merck, Viiv, Immunocore, Vaxxinity, Biotron, Esfam and Abivax; R.L. is an employee of the International AIDS Society; M.d.J. was paid as a consultant by the International AIDS Society. S.C., R.B.J., C.T. and N.A. have no interests to declare.

Additional information

Peer review information Nature Medicine thanks Ravindra Gupta and the other, anonymous, reviewers for their contribution to the peer review of this work. Karen O’Leary was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Deeks, S.G., Archin, N., Cannon, P. et al. Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021. Nat Med 27 , 2085–2098 (2021). https://doi.org/10.1038/s41591-021-01590-5

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Accepted : 27 October 2021

Published : 01 December 2021

Issue Date : December 2021

DOI : https://doi.org/10.1038/s41591-021-01590-5

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Research & training, advances in hiv/aids research.

HIV virions budding and releasing from an infected cell.

For an update on what medical science is doing to fight the global HIV/AIDS pandemic, read a Parade article by NIH Director Francis S. Collins and NIAID Director Anthony S. Fauci, AIDS in 2010: How We're Living with HIV .

Over the past several decades, researchers have learned a lot about the human immunodeficiency virus (HIV) and the disease it causes, acquired immunodeficiency syndrome (AIDS). But still more research is needed to help the millions of people whose health continues to be threatened by the global HIV/AIDS pandemic.

At the National Institutes of Health, the HIV/AIDS research effort is led by the National Institute of Allergy and Infectious Diseases (NIAID). A vast network of NIAID-supported scientists, located on the NIH campus in Bethesda, Maryland, and at research centers around the globe, are exploring new ways to prevent and treat HIV infection, as well as to better understand the virus with the goal of finding a cure. For example, in recent months, NIAID and its partners made progress toward finding a vaccine to prevent HIV infection. Check out other promising areas of NIAID-funded research on HIV/AIDS at http://www.niaid.nih.gov/topics/hivaids/Pages/Default.aspx .

Other NIH institutes, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute on Alcohol Abuse and Alcoholism, also support research to better control and ultimately end the HIV/AIDS pandemic. Some of these researchers have found a simple, cost-effective way to cut HIV transmission from infected mothers to their breastfed infants. Others have developed an index to help measure the role of alcohol consumption in illness and death of people with HIV/AIDS.

Scanning electron micrograph of HIV particles infecting a human T cell.

Find out more about these discoveries and what they mean for improving the health of people in the United States and all around the globe.

This page last reviewed on August 20, 2015

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Future Directions for HIV Treatment Research

A major goal of NIAID-supported research on HIV treatment today is to develop long-acting therapies that—unlike current antiretrovirals, which require daily dosing—could be taken only once a week, once a month, or even less often. Such long-acting therapies might be easier for some people to stick to than daily pills, and might also be less toxic and more cost effective. The three types of agents under study are long-acting drugs, broadly neutralizing antibodies, and therapeutic vaccines.

Long-Acting Drugs

NIAID-supported scientists aim to develop a new array of drugs for HIV treatment that include longer-acting pills as well as alternative formulations such as injections, patches, and implants. The complexity of developing such products has led NIAID to create a consortium of experts who can facilitate relationships among the many types of researchers needed to translate an idea for a long-acting HIV drug into a workable solution. Called LEAP, for Long-Acting/Extended Release Antiretroviral Resource Program, the consortium includes scientists and clinicians from academia, industry, and government, as well as patient advocates. Read more about LEAP.

NIAID also will investigate the effectiveness of two investigational long-acting HIV drugs, rilpivirine LA and cabotegravir LA, in people for whom adhering to conventional antiretroviral therapy has been a challenge. Another study is planned to test whether the combination of monthly injections of cabotegravir LA and monthly infusions of an NIAID-discovered broadly neutralizing antibody called VRC01LS can keep HIV suppressed in people whose infection was previously controlled by antiretroviral therapy. 

Broadly Neutralizing Antibodies

Scientists at the NIAID Vaccine Research Center (VRC) and NIAID-supported scientists at other institutions are developing and testing multiple antibodies for the treatment of HIV. Antibodies are good candidates for treatment because they have few side effects and can be modified to ensure they last a long time in the body, suggesting that dosing could be every other month or even less often. Importantly, the antibodies under investigation can powerfully stop a wide range of HIV strains from infecting human cells in the laboratory and thus are known as broadly neutralizing antibodies, or bNAbs.

In the context of treatment, bNAbs can potentially thwart HIV in three ways:

  • By binding directly to the virus, preventing it from entering a cell and accelerating its elimination.
  • By binding to an HIV-infected cell, recruiting immune-system components that facilitate cell killing.
  • By binding to a key fragment of HIV, forming a complex that may lead to the stimulation of immune cells in a manner similar to a vaccine, thereby preparing the immune system for future encounters with the virus.

Clinical studies have established that giving infusions of certain bNAbs to people living with HIV can suppress the virus, albeit to a limited degree. Further studies have shown that treating people living with HIV with just one bNAb fosters the emergence of HIV strains that are resistant to the antibody. Thus, just as antiretroviral therapy requires a combination of drugs to effectively suppress HIV, it appears that antibody-based therapy will require a combination of either multiple bNAbs or bNAbs and long-acting drugs to suppress the virus. Studies in monkeys infected with a simian version of HIV have already demonstrated that combinations of complementary bNAbs powerfully suppress the virus for an extended period. NIAID is now funding and conducting clinical trials of this strategy for treating HIV in people.

In addition, scientists are engineering changes to known bNAbs to optimize them for HIV treatment and prevention applications. These changes are designed to increase the number of HIV strains an antibody can block, how long the antibody lasts in the body, how powerfully the antibody attaches to the virus, and how efficiently the antibody triggers the immune system to attack both the virus and HIV-infected cells.

Therapeutic HIV Vaccines

Perhaps the ideal treatment for HIV infection would be a therapeutic vaccine. Unlike a vaccine designed to prevent HIV infection, a therapeutic vaccine would be given to people already infected with the virus. Such a vaccine would stimulate the immune system to be ready to control any future emergence of HIV and thereby end the need for further therapy, perhaps save periodic booster shots. Such an approach could lead to sustained viral remission , meaning treatment or vaccination that would result in prolonged undetectable levels of HIV without regular antiretroviral therapy.

The presence of rare people living with HIV who can control the virus naturally either from the time of infection or after halting antiretroviral therapy is evidence that a therapeutic vaccine could theoretically alter the immune system to achieve long-term control of HIV. Nevertheless, attempts to create effective therapeutic HIV vaccines have so far been unsuccessful. To help improve results, NIAID is working to advance the underlying science—in particular, to improve understanding of immune responses that sustainably suppress HIV and to improve the potency of those responses.

Three of the NIAID-funded Martin Delaney Collaboratories are pursuing strategies that involve therapeutic vaccines to achieve long-term control of HIV or reduction of the reservoir of all virus-carrying cells. Read more about the  Martin Delaney Collaboratories .  

Future Directions for Developing Daily HIV Drugs

At the same time, NIAID continues to support research to develop new drugs with unique mechanisms of action for daily antiretroviral therapy. Such drugs likely would be effective against HIV strains with resistance to other drug types.

For example, basic NIAID-supported research contributed to development of the experimental drug islatravir (also known as EFdA or MK-8591), which belongs to a class of drugs known as nucleoside reverse transcriptase translocation inhibitors, or NRTTIs. NIAID research also contributed to the development of maturation inhibitors, investigational drugs that target the same stage of the HIV lifecycle as protease inhibitors but act by a different mechanism.

Researchers also are attempting to target other parts of the HIV lifecycle. For example, the experimental inhibitor fostemsavir blocks HIV from infecting immune cells by attaching to the gp120 protein on the virus’ surface. Another example is development of capsid assembly inhibitors, which halt construction of the viral capsid, the protein shell that encloses HIV’s genetic material.

For more information on investigational antiretroviral treatments, see the AIDS info Drug Database.

a depiction of an HIV cell

Healthline: New HIV variant discovered: May be more infectious and severe

Uc expert says current treatments are still effective.

headshot of Bill  Bangert

New research from the University of Oxford finds a new variant of HIV, the virus that causes AIDS, that is potentially more infectious and could more seriously affect the immune system. So far, 109 people, most of whom live in the Netherlands, have the variant.

The new strain, called the VB variant, damages the immune system, weakening people’s ability to fight everyday infections and diseases much faster than the previous HIV strains, scientists say.  It also means that people who contract the new variant may develop AIDS faster.

In a story published by Healthline, Carl Fichtenbaum, MD, of the Division of Infectious Diseases at the UC College of Medicine was one of the experts cited reacting to this new variant. 

Carl Fichtenbaum, MD, of the Division of Infectious Diseases at the UC College of Medicine/Photo/Joe Fuqua II/UC Creative + Brand

Fichtenbaum told Healthline that it has been known for decades that some individuals get sicker quicker than others.

“The amount of virus measured in a drop of blood is a surrogate of disease progression. The higher the amount, the more likely someone will progress and become ill,” Fichtenbaum told Healthline.

“We suspect many times this is because the type of HIV they got was more aggressive or virulent,” he said. “Our practice is the same regardless of variant — get tested right away and start treatment.”

He noted that there is “no evidence” that the current treatments won’t work.

Fichtenbaum explained that reducing the risk of infection begins with sex with a condom or other barrier method.

“Know your status of HIV and those you have sex with by getting tested first; use condoms for sex; don’t share any needles or paraphernalia for injection drug use,” he said. “Those at higher risk can use PrEP or Pre-exposure prophylaxis.”

Fichtenbaum said FDA-approved treatments for people living with HIV include a tenofovir/emtricitabine combination tablet daily and cabotegravir injections every 2 months.

“Those individuals that have HIV can take their medications and be ‘undetectable’ on their viral load, which eliminates the chance of HIV transmission,” he said. “Hence the slogan U=U; undetectable equals untransmittable.”

Read the entire story here .

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CDC provides national leadership for HIV prevention research, including the development and evaluation of HIV biomedical and behavioral interventions to prevent HIV transmission and reduce HIV disease progression in the United States and internationally. CDC’s research efforts also include identifying those scientifically proven, cost-effective, and scalable interventions and prevention strategies to be implemented as part of a high-impact prevention approach for maximal impact on the HIV epidemic.

The AIDS epidemic, although first recognized only 20 years ago, has had a profound impact in communities throughout the United States.

The Serostatus Approach to Fighting the HIV Epidemic: Prevention Strategies for Infected Individuals R. S. Janssen, D. R. Holtgrave, and K. M. De Cock led the writing of this commentary. R. O. Valdiserri, M. Shepherd, and H. D. Gayle contributed ideas and helped with writing and reviewing the manuscript.

Reports

CDC has provided funding to HIV partners to help implement programs that will help curb the increase of HIV infections. These programs facilitated with our partners and grantees are critical in the goal of eliminating HIV infection in the United States.

Research

CDC has researched several HIV prevention interventions that have proven effective in helping to prevent HIV infection in certain populations and communities.

Demonstration Projects

CDC has worked with key cities to create effective policies and programs to curb the tide of HIV infections in those cities. These cities have higher rates of HIV due to a number of factors therefore making them key locations for studies.

MMP

The Medical Monitoring Project (MMP) is a surveillance system designed to learn more about the experiences and needs of people who are living with HIV. It is supported by several government agencies and conducted by state and local health departments along with the Centers for Disease Control and Prevention.

  • Assessment of 2010 CDC-funded Health Department HIV Testing Spending and Outcomes pdf icon [PDF – 359 KB]
  • HIV Testing Trends in the United States, 2000-2011 pdf icon [PDF – 1 MB]
  • HIV Testing at CDC-Funded Sites, United States, Puerto Rico, and the U.S. Virgin Islands, 2010 pdf icon [PDF – 691 KB]
  • HIV Prevention Funding Allocations at CDC-Funded State and Local Health Departments, 2010 pdf icon [PDF – 792 KB]

Cost-effectiveness of HIV Prevention

  • The cost-effectiveness of HIV prevention efforts has long been a criterion in setting program priorities. The basic principle is straightforward: choose those options that provide the greatest outcome for the least cost.
  • The fact sheet Projecting Possible Future Courses of the HIV Epidemic in the United States pdf icon compares the cost-effectiveness of three different prevention investment scenarios.

The HIV/AIDS Prevention Research Synthesis (PRS) Project identifies evidence-based HIV behavioral interventions (EBIs) listed in the Compendium of Evidence-Based HIV Behavioral Interventions to help HIV prevention planners and providers in the United States choose the interventions most appropriate for their communities.

  • On January 1, 2012, CDC began a new 5-year HIV prevention funding cycle with health departments, awarding $339 million annually.
  • The STD/HIV National Network of Prevention Training Centers provides training for health departments and CBOs on the HIV prevention interventions.
  • HIV by Group
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Researchers find new pathway for HIV invasion of cell nucleus

The researchers also identified three proteins that are needed for the virus to carry out the invasion and have in turn synthesized molecules (potential drugs) that can target one of the proteins, potentially leading to new treatments for AIDS.

"We have revealed a protein pathway that appears to have a direct impact on diseases, which opens up a new area for potential drug development," says the study's senior author Aurelio Lorico, MD PhD, Professor of Pathology and interim Chief Research Officer at Touro University Nevada College of Osteopathic Medicine.

HIV infection requires the virus to enter a cell and gain access to the well-guarded nucleus in order for the viral components to be integrated into the healthy cell's DNA. But how the viruses get past the protective membrane is not well understood and is the subject of much debate.

The newly identified pathway begins with HIV entering a cell wrapped inside a membrane package, called an endosome. The virus-containing endosome then pushes the protective nuclear membrane inward, forming an indentation known as a nuclear invagination. The endosome then moves inside the invagination to its inner tip, where the virus then slips into the nucleus.

The study found that three proteins were critical to the invasion: One protein (Rab7) is located on the membrane of the endosome, the second (VAP-A) is on the nuclear membrane where the invagination occurs, and the third (ORP3) connects the first two proteins together. An interaction among the three proteins is needed for the invasion to be successful, so targeting any of these proteins could halt the infection. The team has synthesized and tested molecules that interrupt the interaction among the proteins. The researchers observed that, in the presence of these molecules, HIV replication does not occur.

This pathway for nuclear access was first discovered in the team's research on cancer metastasis and is likely involved in other diseases as well.

"This is an entirely new pathway and we have developed molecules (drugs) that block it," says Lorico. "Although our research is at a pre-clinical stage, it is likely that the new drugs synthesized may have therapeutic activity in AIDS, other viral diseases, and possibly metastatic cancer and other diseases where nuclear transport is involved." The team is currently looking at the pathway's role in Alzheimer's disease and metastasis of many types of cancer.

"Because the pathway we found may apply to many types of disease, there is a tremendous amount of work that needs to be done to understand the full benefits of this research," says Dr. Denis Corbeil, co-leading author of the study, research group leader at the Biotechnology Center (BIOTEC) of TUD Dresden University of Technology in Germany.

"The ground-breaking research of Dr. Lorico and his team is a testimony to the importance that Touro University gives to its mission of service to humanity. The potential therapeutic applications of this new pathway to improve patient care are immense and may help us better navigate the next pandemic," said Dr. Alan Kadish, Touro University President.

  • HIV and AIDS
  • Infectious Diseases
  • Diseases and Conditions
  • Cell Biology
  • Molecular Biology
  • Natural killer cell
  • Somatic cell nuclear transfer
  • Embryonic stem cell
  • Chemotherapy

Story Source:

Materials provided by Technische Universität Dresden . Note: Content may be edited for style and length.

Journal Reference :

  • Mark F. Santos, Germana Rappa, Jana Karbanová, Patrizia Diana, Girolamo Cirrincione, Daniela Carbone, David Manna, Feryal Aalam, David Wang, Cheryl Vanier, Denis Corbeil, Aurelio Lorico. HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells . Nature Communications , 2023; 14 (1) DOI: 10.1038/s41467-023-40227-8

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This page last reviewed on March 19, 2024

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Breaking news, genetic tool eliminates hiv from infected cells, new research shows: ‘cure strategy’.

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Scientists have successfully zapped HIV out of infected cells — raising hopes of a cure for the chronic disease.

The team from Amsterdam UMC used gene-editing technology to eliminate all traces of the virus from cells in the laboratory, the European Congress of Clinical Microbiology and Infectious Diseases announced Tuesday.

“These findings represent a pivotal advancement towards designing a cure strategy,” team leader Dr. Elena Herrera-Carrillo and fellow authors Yuanling Bao, Zhenghao Yu and Pascal Kroon said in a statement.

To accomplish this revolutionary feat, the Dutch research team turned to the Nobel Prize-winning CRISPR-Cas, the gene-editing technology capable of altering the DNA of animals, plants and microorganisms with extremely high precision.

Dr. Elena Herrera-Carrillo lead the team from Amsterdam UMC to use gene-editing technology to eliminate all traces of the HIV virus from cells in the laboratory

The tool — described by the scientists as “molecular scissors” — was used to cut DNA at designated spots to completely delete the HIV infections from cells, even in “hidden” HIV reservoir cells.

HIV is incredibly difficult to treat because of the virus’ ability to integrate its genome into the host’s DNA. It is also known to infect different types of cells and tissues in the body, each with its own unique environment and characteristics, making a one-type-cure-all nearly impossible.

The team focused on parts of the virus that stay the same across all known HIV strains, an approach that aims to provide a broad-spectrum therapy capable of fighting different HIV variants.

“Our aim is to develop a robust and safe combinatorial CRISPR-Cas regimen, striving for an inclusive ‘HIV cure for all’ that can inactivate diverse HIV strains across various cellular contexts,” the authors wrote.

Despite their exhibiting findings, the scientists warned much more research will be needed before the zapping can be put into practice.

The team focused on parts of the virus that stay the same across all known HIV strains, an approach that aims to provide a broad-spectrum therapy capable of fighting different HIV variants.

The team’s next goal is to optimize the delivery route to target the majority of the HIV reservoir cells, while avoiding those that aren’t infected.

“This strategy is to make this system as safe as possible for future clinical applications. We hope to achieve the right balance between efficacy and safety of this CURE strategy. Only then can we consider clinical trials of ‘cure’ in humans to disable the HIV reservoir.”

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“While these preliminary findings are very encouraging, it is premature to declare that there is a functional HIV cure on the horizon,” Herrera-Carrillo’s team wrote.

Even with the groundbreaking technology, long-term treatment for HIV would continue to involve potent antiviral drugs, they warned.

The tool -- described by the scientists as "molecular scissors" -- was used to cut DNA at designated spots to completely delete the HIV infections from cells, even in "hidden" HIV reservoir cells.

HIV is a resilient infection that can rebound from established reservoirs when treatment is halted.

Those infected can live normal lives with adequate treatment, but the virus can pose lifelong health issues and even death when cared for too late.

More than 40 million people have died from the virus worldwide since the HIV epidemic started in 1981, according to the World Health Organization.

The death toll has dropped significantly in decent decades — 630,000 infected people across the globe succumbed to the disease in 2022, with 39 million recorded as living with the disease that year.

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Dr. Elena Herrera-Carrillo lead the team from Amsterdam UMC to use gene-editing technology to eliminate all traces of the HIV virus from cells in the laboratory

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Scientists and clinicians whose discoveries have shaped the understanding of HIV disease will provide updates on the status of HIV/AIDS research and patient care and discuss approaches to overcome major remaining challenges at a scientific symposium hosted by Hood College in partnership with the Frederick National Laboratory for Cancer Research (FNL) on September 23-25.   

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"HIV in 2024: Progress, Problems and Prospects" will be held on the Hood campus in Frederick, Maryland, and will emphasize aspects of HIV research with the potential to impact clinical care and prevention approaches, including vaccines, as well as research on Kaposi's sarcoma-associated herpesvirus (KSHV), which can cause a variety of tumors and disease syndromes, particularly in individuals with HIV-related immunodeficiency.  

Led by FNL investigators Mary Carrington, Ph.D. and Jeffrey Lifson, M.D. , both known for their many contributions to research on HIV/AIDS, the symposium is for students, trainees, active researchers, and clinicians, including those who may not presently be engaged directly in HIV research. 

“We probably know more about HIV than any other virus and more about the disease it causes than any other viral disease,” said Carrington, an internationally recognized expert in immunogenetics of disease, including HIV/AIDS, and head of FNL’s Basic Science Program . “Many of the concepts, approaches, and general knowledge pertaining to HIV/AIDS that will be covered in the symposium are applicable and shed light on other human diseases.” 

Lifson is director of the AIDS and Cancer Virus Program at FNL. His work involves a combination of virology and immunology including the development of experimental model systems, with the aim of understanding HIV pathogenesis and approaches to prevent and treat HIV infection. 

Carrington and Lifson have assembled a program of noted HIV researchers for the symposium. “All of the speakers are world-renowned experts in their fields of expertise,” Lifson said. “Each has made significant contributions to our understanding of HIV disease, including advances in basic science, prevention, and treatment.” 

Salim S. Abdool Karim, a physician, scientist, and director of the Centre for AIDS Program of Research in South Africa , whose work provided proof-of-concept that antiretroviral drugs can prevent sexually transmitted HIV infection, will deliver the keynote address on Monday, Sept. 23 at 7:30 p.m. 

“With strong ties to the global HIV community, Drs. Lifson and Carrington have put together an outstanding scientific program covering the very latest in basic and clinical research,” said Ethan Dmitrovsky, M.D. , FNL director and president of Leidos Biomedical Research, Inc., which operates the FNL for the National Cancer Institute. “This meeting will give attendees current, cutting-edge information about the HIV/AIDS field.” 

Symposium topics include epidemiology of HIV, vaccine and non-vaccine prevention, treatment of HIV infection, KSHV and the HIV reservoir. Previous FNL-Hood symposia have explored AI in cancer research and imaging science in cancer biology.  

The symposium will begin Monday, September 23 with a reception at 5:30 p.m. followed by Abdool Karim’s lecture, which is open to the public.  

To learn more and to register for the event, please visit the symposium website . 

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Half of those with HIV in developed countries are at least age 50, at higher risk of frailty and multiple comorbidities

by European Society of Clinical Microbiology and Infectious Diseases

older people

A new research review to be presented at a pre-congress day for this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2024) will focus on the growing prevalence of HIV in older adults, with—using England as an example—half of adults accessing care aged now 50 years and older, and around 1 in 11 aged 65 years and older. Similar trends exist in Italy and other countries of Western Europe. Older adults with HIV in all countries are also more likely to have comorbidities and become frail earlier than older adults without HIV.

Presenter Professor Giovanni Guaraldi, University of Modena and Reggio Emilia, Modena, Italy, will also discuss the problem of more older people being diagnosed with HIV (one in 5 new diagnoses in those aged 50 and over) and late diagnosis in those older people, with (again using the example of England) around half of those cases newly diagnoses in the over-50s presenting with white blood cell CD4 count below 350 cells per mm 3 of blood within 3 months of diagnosis, increasing their risk of mortality in the following year five-fold.

Despite the challenges, Prof. Guaraldi will also highlight the progress made, with the difference in remaining life expectancy comparing those people living with HIV and those without HIV infection aged 21 years decreasing from 22 years in 2003-06 down to 9 years in 2014-2016. Yet across that same period, there was no change in the difference of years lived without developing other conditions (multimorbidity) with those living with HIV living 15 fewer years without multimorbidity compared with those not infected. Today, in another sign of progress, a young person diagnosed with HIV promptly can expect the same life expectancy as those not living with HIV.

By age 65 years, around 70% of those living with HIV for 20 years or more are living with multiple other conditions, compared with around 50% for those infected for less than 20 years and close to 40% for those not living without HIV. These figures steadily increase as those with HIV age, but the gap narrows between those with and without HIV (see graph in presentation). A similar trend is shown for polypharmacy (taking multiple prescribed drugs) in those living with HIV.

Prof. Guaraldi will also discuss the hidden phenomenon of accelerated aging, or "early frailty" in those living with HIV. Frailty is a clinical syndrome based on presence of specific signs and symptoms, including weight loss, exhaustion, lack of physical activity, decreasing grip strength, and walking speed. He will review a study showing frailty levels higher in people living with HIV compared with those not living with HIV, across all age groups from age 50 years and up, with rates some five times higher in those aged 65+. Another study shows older adults living with HIV twice as likely to become frail as their HIV negative peers.

He will discuss that frailty and poor outcomes are not inevitable, and ways of avoiding this include early diagnosis of HIV and initiation of antiretroviral treatment (to avoid risk of rapid progression and cognitive impairment), but also a careful analysis of all their other medications and taking people off them (deprescribing) where possible. He will also cover drugs that should be avoided in older people with HIV where possible, due to drug-drug interactions and also drugs that increase the risks of frailty. Examples in this extensive list include the alfalitics drug class used for treating high blood pressure, and benzodiazepines that can increase the risk of falls.

Finally, he will refer to the social and care challenges faced by older people living with HIV, explored in the recent paper he co-authored in The Lancet HIV , discussing, among other issues, the problems that they can face entering long-term aged care facilities and opening up about their diagnosis to new doctors and people that they are not familiar with—and an array of other problems, including exacerbated challenges of daily living, mental health problems including "survivor guilt" and stigma, and the increasing isolation caused by the COVID-19 pandemic.

Prof. Guaraldi and colleagues explain, "Ageism can enhance several HIV-related issues, including self-inflicted stigma, and loneliness. At-risk communities are particularly susceptible to experiencing these aspects. Ageism can be considered the last pillar of the stigma cascade affecting older people living with HIV, and also the most important barrier to achieving healthy aging in people living with HIV."

Among the many recommendations, the researchers advise that "clinical care systems need to be reshaped to meet the needs of older people living with HIV, including geriatric syndrome screening, integrated care, and support and referral systems that include provision of adequate time for medical visits with a focus on improving wellness and functional status," and that "HIV doctors and clinicians should receive training on how to provide comprehensive care for older people living with HIV."

They say, "The model of care for older people living with HIV needs to extend beyond virological success by adopting a geriatric mindset, which is attentive to the challenge of ageism and is proactive in promoting a comprehensive approach for the aging population."

Prof. Guaraldi will also emphasize that with the advances in care and treatment, people living with HIV can age healthily with the right support. He will refer to the first ever known patient with HIV to reach age 100 years, The "Lisbon Patient" Miguel, who died in August 2019, months after celebrating his 100th birthday. He did not have multiple other conditions or polypharmacy, and lived alone and independently, and had never in his life been admitted to hospital.

Prof. Guaraldi concludes, "We are now in an entirely new era where living into your 70s, 80s and even 90s with HIV is now possible and becoming more and more common. We must make sure that we do everything we can, socially, physically and medically, to ensure people living with HIV live as healthy a life as possible as they reach their later years."

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Psychology professor leads field in HIV and mental health research

By Adrianne Gonzalez 03-29-2024

Steven Safren , professor of psychology and director of the Center for HIV and Research in Mental Health (CHARM) at the University of Miami, was recognized by the Faculty Senate with the  2023–24 Distinguished Faculty Scholar Award for a lifetime of distinguished accomplishments in clinical practice and research. 

After joining the University of Miami faculty in 2015, Safren founded CHARM — an interdisciplinary center between the College of Arts and Sciences, Miller School of Medicine, and the School of Nursing and Health Studies. Funded by the National Institute of Mental Health, the center is designated as a full HIV/AIDS facility and one of seven in the nation.

Nominated for the Distinguished Faculty Scholar Award by Philip M. McCabe , professor and chair of the Department of Psychology, Safren is lauded for his exceptional proactivity, extensive funding success, and leadership in the field. “He is a truly exceptional scholar, teacher, and University citizen. He has my highest recommendation,” said McCabe.

Safren earned his Ph.D. in clinical psychology from the University at Albany State University of New York and trained at Massachusetts General Hospital, Harvard Medical School specializing in cognitive behavior therapy. 

Reflecting on his most memorable moments at the University of Miami, Safren emphasizes his pride in witnessing his students' achievements during the commencement ceremonies and believes that both students and graduates must narrow their focus. “ Find a piece of what you are studying that you really enjoy, and do more of that,” he shared.

The 2023–24 Faculty Senate Awards Ceremony will be held in person on Monday, April 8, at 5 p.m. on the Coral Gables Campus.  Learn more about the awards ceremony.

This profile is part of a 2023–24 Faculty Senate Awards series recognizing all awardees.

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Home  /  News  /  Grants and Awards  /  Graduate Studies

Graduate Students’ Discoveries Shine During Best Research Awards

Best Research Award winners (from left) Skye Montoya, Oandy Naranjo, Olivia Osborne and Jiaqi Liu.

Each year, the University of Miami Miller School of Medicine’s Medical Faculty Association honors Ph.D. students with Best Research Awards. This year, students researching cancer, HIV and cerebral amyloid angiopathy garnered the awards.

“The annual Best Research Awards highlight the powerful and innovative research our Ph.D. students conduct,” said Ana Fiallos, Ph.D., director of career services for the Office of Graduate Studies. “While we can only have four winners, the recognition is a testament to the hard work and creativity our students and faculty show every day.”

Fighting Brain Tumors

Fourth-place awardee Jiaqi Liu studies gliomas, a type of brain tumor, in the Zhai Lab. Her work has shown that the protein NMNAT, an enzyme crucial in the final step of nicotinamide adenine dinucleotide (NAD+) synthesis, plays a significant role in the growth and progression of gliomas.

Experiments with fruit flies which were validated in human glioma cells showed that increased NMNAT activity allowed glial cells with harmful mutations to survive and multiply. This work could offer two advantages. NMNAT could be used as a biomarker to identify patients at high risk for cancer progression. It could also be used as a therapeutic target.

“It’s possible to develop an inhibitor that targets this protein to suppress brain tumors before they become deadly,” said Liu. “We could potentially use such an inhibitor in the brain after surgery to help eliminate residual cancer.”

HIV-Associated Neurocognitive Disorders

Third place went to Oandy Naranjo in the Toborek Lab. Naranjo investigates the consequences of HIV-1 infection and focuses on HIV-associated neurocognitive disorders. He is studying cells in the blood-brain barrier (BBB), called pericytes, that harbors HIV and may contribute to cognitive loss.  

Anti-retroviral drugs do not penetrate the BBB as well as other parts of the body. Infected cells produce viral particles, which generate inflammation. Though HIV patients can live almost normal life spans, this long-term inflammation can have a powerful impact on the brain. Naranjo wants to understand how pericytes behave differently when infected and hopes these insights will lead to treatments.

“We created a big database of latent, active and uninfected cells and how they’re different from each other,” said Naranjo. “This could give us insights into how specific genes could be used to treat HIV-associated neurocognitive disorders.”

Cerebral Amyloid Angiopathy

Olivia Osborne, who placed second, also works in the Toborek Lab, studying the molecular mechanisms that affect post-stroke neurogenesis (brain tissue growth) in people with cerebral amyloid angiopathy (CAA). Osborne was awarded an F31 fellowship from the National Institutes of Health to advance her dissertation on “Ischemic Stroke in Cerebral Amyloid Angiopathy: Microvascular Injury and Recovery.”

In CAA, amyloid beta (Aβ) proteins, which have been linked to Alzheimer’s disease, weaken small blood vessels, sometimes causing bleeding. Osborne wants to understand how these mechanisms affect people who have suffered a stroke.

“My central hypothesis is that Aβ accumulation in cerebral vasculature exacerbates ischemic stroke outcomes and delays post-stroke recovery,” said Osborne. “My work focuses on the blood vessels after damage occurs. There’s some sort of dysregulation that might disrupt signaling to other cells in the area and delay recovery. If we can find that signaling pathway, we could potentially target it therapeutically.”

Chronic Lymphocytic Leukemia

Skye Montoya from the Taylor Lab won top Best Research Award honors. She studies mutations in chronic lymphocytic leukemia (CLL), focusing on Bruton’s tyrosine kinase (BTK), an enzyme that drives cancer growth.

Montoya wants to identify small molecules that could regulate BTK and slow or even stop CLL. Cancers have a bad habit of learning how to resist targeted therapies, and Montoya and colleagues are trying to figure out ways to overcome that resistance. Montoya was first author on a recent paper, published in the journal “Science,” that identified previously unknown BTK mutations and showed a potential therapy (NX-2127) could be effective.

“Each BTK mutant we study can cause resistance to multiple BTK inhibitors, which can really limit therapeutic options for patients harboring these mutations,” said Montoya. “We were all excited to see positive responses in both cell lines and patients, regardless of BTK mutational status.”

Tags: Best Research Awards , Medical Faculty Association

Graduate Student Creates App to Aid Brain Recovery

Olivia Osborne created a mobile app that tracks cognitive function and dovetails with her research on stroke and the brain.

Mentor and Mentee: A Win-Win

With several collaborative studies behind them, Justin Taylor, M.D., and mentee Skye Montoya look forward to even more promising research.

Ph.D. Students Receive Research Internships at Eli Lilly, Merck

Three Miller School of Medicine Ph.D. students will be extending their training after accepting internships at the prominent companies.

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  24. Genetic tool eliminates HIV from infected cells, new research shows

    Scientists have successfully zapped HIV out of infected cells — raising hopes of a cure for the chronic disease. The team from Amsterdam UMC used gene-editing technology to eliminate all traces ...

  25. Global experts to illuminate state of HIV/AIDS research and patient

    Scientists and clinicians whose discoveries have shaped the understanding of HIV disease will provide updates on the status of HIV/AIDS research and patient care and discuss approaches to overcome major remaining challenges at a scientific symposium hosted by Hood College in partnership with the Frederick National Laboratory for Cancer Research (FNL) on September 23-25.

  26. Half of those with HIV in developed countries are at least age 50, at

    A new research review to be presented at a pre-congress day for this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2024) will focus on the growing prevalence ...

  27. Psychology professor leads field in HIV and mental health research

    By Adrianne Gonzalez 03-29-2024. Steven Safren, professor of psychology and director of the Center for HIV and Research in Mental Health (CHARM) at the University of Miami, was recognized by the Faculty Senate with the 2023-24 Distinguished Faculty Scholar Award for a lifetime of distinguished accomplishments in clinical practice and research.

  28. FACT SHEET: President Biden Issues Executive Order and Announces New

    This includes the launch of a new NIH-wide effort that will direct key investments of $200 million in Fiscal Year 2025 to fund new, interdisciplinary women's health research—a first step ...

  29. Graduate Students' Discoveries Shine During Best Research Awards

    This year, students researching cancer, HIV and cerebral amyloid angiopathy garnered the awards. "The annual Best Research Awards highlight the powerful and innovative research our Ph.D. students conduct," said Ana Fiallos, Ph.D., director of career services for the Office of Graduate Studies. "While we can only have four winners, the ...