Reversing HIV Latency and Decreasing the Viral Reservoir: Clues from Cancer

Research Question

Study lead author Dr. Sharon Lewin

HIV persists in a dormant state primarily in T cells expressing surface proteins known as immune checkpoint (IC) molecules. These surface molecules normally act as brakes that prevent an overly reactive immune response. In the setting of HIV, ICs might hamper efforts to cure by keeping the virus in immune cells in a latent state or preventing effective anti-HIV immune responses.

Based on anecdotal reports involving patients with both HIV and cancer who were treated with certain immune-modifying cancer drugs, researchers have raised the possibility that “immune checkpoint inhibitors” might be able to deplete reservoirs of latently HIV-infected cells. Such reservoirs are the prime obstacle to an HIV cure.

These inhibitors—antibodies to two normal cell proteins known as PD-1 and CTLA-4—when used in combination, might be able to both activate HIV from latently infected cells and boost HIV-specific immunity, leading to the destruction of such cells.

Findings

A group led by Dr. Sharon Lewin from Melbourne, Australia, studied 40 people living with HIV (PWH) on effective antiretroviral therapy who developed advanced cancers. They were being followed in a study of cancers in PWH supported by the National Institutes of Health.

These individuals required treatment with an anti-PD-1 drug with or without an anti-CTLA-4 drug, as part of the usual management of such cancers. Levels of active HIV and estimates of the size of the latent reservoir were determined prior to and after the first and fourth doses of these agents.

Although use of a PD-1 inhibitor had no effect, its combination with an anti-CTLA-4 drug led to reversal of latency and a small but statistically significant decrease in the latent reservoir.

Impact

The authors concluded that this combination treatment “warrants further investigation [as it] may potentially eliminate cells containing replication-competent HIV.”

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/33677480

Dr. Laurence is amfAR’s senior scientific consultant.

Risks and Potential Benefits of Participating in Cure Research

Research Question

Study co-author Dr. Karine Dubé

In order to document whether an intervention designed to cure HIV is successful, an intensively monitored pause of the participant’s antiretroviral treatment (ART) is almost certainly required. Researchers hope that alternatives to stopping ART that accurately predict who is most likely to benefit from a cure strategy will be found, but finding those alternatives will also require monitored pauses in ART. Perceptions of cure trial participants concerning personal and community risks and benefits are relevant to such studies and have received little attention. 

Findings

A National Institutes of Health trial of people living with HIV taking effective ART in the U.S. and Thailand involved a pause in treatment in order to identify possible markers predicting time to rebound of HIV when no intervention had been administered.

Researchers used a questionnaire to evaluate participant perceptions before and after initiating that pause. Thirty-two individuals at U.S. trial sites were surveyed, half before and half after the ART interruption. All participants saw a social benefit to participation—“Participating moves researchers closer to finding a cure for HIV”—compared to only half of the respondents who believed there would be any direct benefits to them before the pause.

However, in those who were surveyed after the ART pause, 69% thought that there was a direct benefit. In terms of risks of participation, 81% of individuals in both groups reported concern over risks in participating, particularly side effects and physical pain. Participants also reported concern over safety risks related to experiencing a detectable viral load.

Impact

The authors concluded that “Key messages pertaining to study-related risks and benefits may need to be clarified or reiterated periodically” in cure-related studies involving planned treatment interruptions. One limitation to generalizing these results is that 75% of the participants were White, non-Hispanic, and all except two were male.

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/33472545

Dr. Laurence is amfAR’s senior scientific consultant

Verifying Models and Identifying New Targets for Attacking HIV Latency

Research Question

Study co-author Dr. Steve Yukl

In order to identify potential new ways to overcome HIV latency—the main obstacle to an HIV cure—researchers would ideally study latently infected cells from people living with HIV. Yet the use of latently infected cells taken directly from an infected person has limitations of scale, and cells from tissues other than blood are not easily accessible. The degree to which various test-tube systems for HIV latency accurately reflect what’s happening in an infected person’s cells is unclear, hampering the search for relevant treatments. Therefore, researchers must develop model test-tube systems that recapitulate persistent HIV in people.

Findings

Three test-tube cell models were compared to blood cells obtained from HIV-positive individuals on antiretroviral treatment with undetectable viral loads. All models were able to recapitulate the molecular patterns by which HIV appears to maintain a dormant state. In addition, a common set of some 200 host genes distinguished latently infected cells from cells activated to produce infectious virus in all these cell systems. There was a particular focus on the conversion of HIV DNA into messenger RNA, an early step in the process of making HIV proteins.

Impact

The authors concluded that the genes they identified may represent new targets for treatments designed to silence or activate HIV reservoir cells.

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/33253324

Dr. Laurence is amfAR’s senior scientific consultant.

Prospects for an HIV/AIDS Cure: Opinions of People with HIV and Their Healthcare Providers

Research Question

Study co-author Dr. Sharon Lewin

When people living with HIV (PWH) join clinical trials for cure research, they are often referred by their healthcare providers. It is therefore important to learn how each group views such research, including the need to interrupt antiretroviral therapy (ART) under closely monitored conditions in a process known as analytical treatment interruption (ATI).

Findings

Two online surveys conducted by the Australian HIV Cure Community Partnership questioned 442 PWH and 144 HIV healthcare providers from North America, Western Europe, and Australasia. Interest in, knowledge of, and experience with cure research differed between the two groups. While 37% of PWH had participated in any kind of HIV clinical trial, only 5% had participated in a cure-focused study. Slightly fewer than half were aware of ATI in cure research, and a quarter had ever interrupted their ART, but mostly outside the cure research context.

Of note, 90% of PWH said they would be willing to stop ART for a study. By contrast, although knowledge of ATI was higher among healthcare providers, only 31% were confident they would allow their patients to enroll in such a study, and only a quarter would promote such studies to their patients. These differences tracked with optimism surrounding the development of a cure—more than half of PWH thought a cure could be achieved in the next 10 years, compared to only 19% of healthcare providers. 

Impact

The authors concluded that educational strategies tailored specifically to each group are required to increase understanding of HIV cure research and the role of ATI.

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/33168019

Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.

amfAR Invests in ‘Next Generation’ HIV Cure Intervention

New grant initiative seeks out novel ideas and technologies, borrows from cancer research 

NEW YORK, Nov. 16, 2020 --- amfAR, The Foundation for AIDS Research, has awarded funding to researchers exploring an HIV cure approach that has previously shown promise in cancer therapy. 

The only known cases of HIV cure to date occurred in people living with HIV—the Berlin and London patients—whose blood cancer was treated with a stem cell transplant. Both received stem cells from donors with a genetic mutation that left them with no functional CCR5 protein—the main gateway that enables most types of HIV to enter and infect cells. 

“While we learned a great deal from these cases, it just isn’t possible to apply or adapt this type of procedure to cure everyone who’s living with HIV,” said amfAR Chief Executive Officer Kevin Robert Frost. “Though a number of different avenues are currently being pursued in the search for a cure, we sought research projects that could seed the next generation of potential interventions.”   

Veteran HIV researcher and former amfAR grantee Jerome Zack, Ph.D., of the University of Caliornia, Los Angeles, will employ a new intervention attempting to rid the body of the persistent reservoir of HIV—the ultimate barrier to a cure. Dr. Zack and colleagues will use natural killer (NK) cells in an effort to eliminate cells harboring reservoir virus from the body. NK cells are the foot soldiers of the innate immune system, delivering an immediate and potent counterattack against infectious agents such as HIV. 

These cells can be administered either in their naturally occurring form, or they can be engineered as CAR-NK cells to enhance their ability to kill their targets.  To compare the ability of unaltered and CAR-NK cells to affect the rebound of virus when antiretroviral therapy is withdrawn, the researchers will employ several novel technologies developed by Dr. Zack. These include the insertion of a barcode into viruses so that the fate of each individual virus can be tracked, and use of a latency reversing agent developed in his lab. 

“An important advantage of this approach is that CAR-NK cells—unlike CAR-T cells—have the potential to be designed for off-the-shelf use, vastly simplifying their broad application,” said Dr. Rowena Johnston, amfAR Vice President and Director of Research. 

About amfAR

amfAR, The Foundation for AIDS Research, is one of the world's leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and advocacy. Since 1985, amfAR has invested nearly $575 million in its programs and has awarded more than 3,300 grants to research teams worldwide.

Mining the Blood for Markers of the Reservoir

By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

Research Question

Study senior author Dr. Galit Alter speaking at amfAR's 2019 Meet the Scientists event

Most people living with HIV (PLH) must take daily antiretroviral therapy (ART) to control the virus, but a rare few known as viremic controllers (VCs) can maintain fairly low viral loads in the absence of ART, and an even smaller number known as elite controllers (ECs) maintain undetectable virus levels without ART. In all cases, a reservoir of mostly inactive virus, largely in tissues that are difficult to access, is the main barrier to an HIV cure.

Antibodies, the most exquisitely sensitive detectors of virus that we have, may hold the key to understanding how ART-free control of HIV can be achieved. And they may even provide an easy-access method to help us understand the size and behavior of the reservoir hidden in inaccessible tissues throughout the body.

Findings

Sixty-four PLH, including 12 ECs, 23 VCs, 17 with undetectable virus on ART, and 12 with detectable virus and no treatment, were studied, along with HIV-negative control subjects. A total of 293 HIV antibody characteristics—such as their quantity, the region of the virus they target, and the antiviral functions they trigger—were tested in the blood of all subjects. These were compared with viral load, and with proviral DNA, as a measure of the size of the HIV reservoir.

Results were analyzed utilizing a machine learning technique that trains a computer to detect patterns in large amounts of data. Unanticipated correlations were found, such as an association of antibody levels against an “accessory” HIV protein, Vif, with reservoir size.

Impact

The authors concluded that “the development of these tools may represent simple biomarkers for the rapid evaluation of changes in viral replication outside of the blood and changes in the reservoir size.”

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/33048992

Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.

HIV Reservoirs in the Blood and Gut Respond Differently to Virus Activators

Research Question

Study co-author Dr. Steven Yukl

Latent infection is the primary obstacle to curing HIV, but differences in infected cell types and other factors specific to different tissue reservoirs may affect response to treatments aimed at eradicating latent infection. For example, it is unclear to what extent different “latency reversing agents,” or LRAs, can influence latency in cells in the blood vs. the gut. This is important as most HIV-infected cells reside in tissues such as the gut.

Findings

Scientists from the amfAR Institute for HIV Cure Research examined cells from the blood and intestinal biopsies of 11 HIV-infected individuals on antiretroviral treatment. They exposed these cells in the test tube to different LRAs along with antiretroviral drugs. They found that one LRA, disulfiram, activated virus in cells from the blood but not from the gut, while another did the opposite, being more active in gut than blood. Based on the mechanism of action of various LRAs, these researchers identified different biochemical pathways linked to HIV activation in blood vs. intestinal cells. Interestingly, this new research could help explain how amfAR’s early support of research on disulfiram as a potential LRA ten years ago ended when the drug showed little success in clinical trials.

Impact

The authors conclude that “it will be critical to evaluate the efficacy of LRAs in both blood and tissues” in order to develop more effective therapeutics in HIV cure strategies.

amfAR’s Role

amfAR was a funder of this research.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32910065

Dr. Laurence is amfAR’s senior scientific consultant.

The Past, Present, and Future of HIV Reservoir Cells

Research Question

Dr. Nadia Roan

The HIV reservoir consists of HIV-infected cells that are difficult to characterize because to date they have been indistinguishable from uninfected cells. Once the HIV inside infected cells is activated, many of the surface and interior characteristics change. While activated reservoir cells are easier to identify and isolate from blood samples, these fundamental changes mean they are no longer typical reservoir cells. Thus the challenge for researchers is to work out what an activated infected cell in the present looked like in the past.

Findings

Researchers from the amfAR Institute for HIV Cure Research, led by Dr. Nadia Roan, combined two technologies. First, they characterized levels of 39 surface and intracellular proteins of activated CD4 T cells in the blood, lymph nodes, and gut of eight individuals on long-term antiretroviral therapy. Next, they used a method previously developed at the Institute to back-calculate the combination of proteins the cells likely possessed immediately prior to stimulation. Using these tools, the researchers discovered a group of eight to ten proteins that, when considered in combination, reliably identified resting HIV reservoir cells. 

Impact

The ability to accurately identify true restingreservoir cells will enable researchers to isolate them from the blood and tissues of people living with HIV so that the effects of curative interventions can be studied more closely. It will also enable doctors to quantify how much reservoir remains after a clinical intervention and will help determine if the person is cured of HIV.

amfAR’s Role

amfAR was a funder of this research.

Original Article

https://pubmed.ncbi.nlm.nih.gov/32990219/

Dr. Johnston is an amfAR vice president and director of research.

A Conversation with the San Francisco Patient

Molecular Pathways to an HIV Cure

Research Question

amfAR grantee Dr. Mohamed Abdel-Mohsen was a co-author of this study.

Special types of sugars called glycans—present on the surface of normal cells—play key roles in the movement of cells through the body and influence their capacity to interact with other cells. But the types of sugars present on cells following HIV infection, and whether they might contribute to the persistence of viral reservoirs, is unknown. 

Findings

Scientists from research groups in the U.S., Australia, and Japan looked at glycans found on the surface of HIV-infected cells that were either inactive or beginning to produce HIV. They found that the surface of HIV-infected CD4+ T cells that were starting to produce HIV had more molecules—known as ligands—composed of the glycan fucose than inactive cells. Fucose has been implicated in many important biologic functions, including immunity and cancer. 

This difference was demonstrated both in test-tube experiments and in T cells obtained directly from people living with HIV who were receiving antiretroviral treatment. The implication is that the two T cell types—those beginning to produce HIV and those maintaining dormant virus—may move through the body, or “traffic,” in very different ways. This trafficking activity may play an important role in maintaining reservoirs of HIV-infected cells throughout the body.

Impact

The authors concluded that the differences they identified “could provide the HIV cure field with vital biological clues into the molecular pathways involved in viral persistence.” 

amfAR’s Role

amfAR was a funder of this study.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32755584

Dr. Laurence is amfAR’s senior scientific consultant.

Exploring Cell Proteins That Block HIV

Research Question

Concept rendering of APOBEC3G protein

Evolution has insured that many mammals—from mice to humans—have cell proteins that can prevent infection by certain viruses, including HIV. One of the most potent of these proteins, identified two decades ago, is APOBEC3G. Unfortunately for humans, HIV has evolved protection—a viral protein that prevents APOBEC3G from attacking HIV in humans, though not in other species.

However, there are other proteins being studied. One is SERINC5, which can attack HIV and a related mouse virus, MLV, in the test tube. Its potency is limited by a countermeasure incorporated into HIV—the Nef protein—but it is unknown whether the antivirus activity of SERINC5 works in the body.

Findings

Researchers genetically engineered mice to delete SERINC5. Mice lacking the protein had higher levels of virus, demonstrating that SERINC5 could block MLV activity in the mouse. The researchers identified sites on the virus that made it susceptible to SERINC5 attack.

Impact

The authors concluded that their findings may help guide development of drugs that target SERINC5 during HIV and related viral infections.

amfAR’s Role

amfAR was a funder of this study.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32665269

Dr. Laurence is amfAR’s senior scientific consultant.

How Does the Immune System Recover After a Stem Cell Transplant?

Research Question

Study co-author Dr. Sharon Lewin

Despite effective antiretroviral therapy, people living with HIV (PLWH) are at increased risk of developing certain types of cancer that require a stem cell transplant for their cure. Such transplants were behind the cures of the Berlin and London patients. Preliminary data suggest that PLWH are at heightened risk for infectious complications due to the way their immune systems recover post-transplant, compared to those without HIV. The mechanism by which this occurs is unknown.

Findings

Six PLWH on antiretroviral therapy and 21 HIV-negative individuals underwent stem cell transplants. No difference was seen in the recovery of CD4+ T cells after the transplant, even though PLWH had lower CD4 cell counts before the procedure. In contrast, much higher numbers of CD8+ killer T cells were found in the HIV-positive group post-transplant. These higher T cell numbers occurred between nine and 12 months post-transplant, and persisted for several years. The researchers found no consistent patterns in the number or function of these cells in the PLWH that they assessed.

Impact

The authors concluded that this study, based on a small number of patients, “highlights how little we know about the clinical course post-transplant for HIV-positive persons,” arguing for more research focused on this population.

amfAR’s Role

amfAR was a funder of this study.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32520987

Dr. Laurence is amfAR’s senior scientific consultant.

Why Do HIV Reservoirs Persist After Stem Cell Transplants?

Research Question

People living with HIV have received stem cell transplants in attempts to cure co-existing leukemia or lymphoma. Three such individuals who received stem cells from donors bearing the rare CCR5-delta32 mutation have been cured of HIV, but other HIV-positive individuals who received stem cell transplants with or without the mutation were not—their virus rebounded within weeks to months after stopping antiretroviral therapy (ART). Researchers are currently investigating why stem cell transplants cure HIV in some cases, but not others.

Co-Principal Investigators Drs. Javier Martinez-Picado (front right) and Annemarie Wensing (center right), pictured with ICISTEM members. Also pictured are Dr. Rowena Johnston (front, second from right) and Dr. Jeffrey Laurence (back row, right) of amfAR.

Findings

Researchers studied 16 HIV-positive individuals on ART who underwent stem cell transplants. As usual, preparatory chemotherapy, along with the transplanted cells, killed almost all immune cells in the transplant recipient. Activated CD4+ T cells—prime targets for infection by any remaining HIV—were the first immune population to recover post-transplant. This was followed, several weeks later, by a very slow expansion of HIV-specific CD8+ “killer” T cells at low levels. These potential killers of HIV-infected cells maintained suboptimal levels for years.

Impact

The fact that a high level of activated CD4+ T cells were first to appear post-transplant, and that there was not a significant anti-HIV CD8+ T cell response, suggests that there is a “window of vulnerability” for replenishing latent HIV reservoirs in the early days following a transplant—and emphasizes maintaining ART for prolonged periods post-transplant.

amfAR’s Role

Researchers affiliated with the amfAR-funded European IciStem consortium conducted this study.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32376772

Dr. Laurence is amfAR’s senior scientific consultant.

When Treatment Stops, Why Can’t the Immune System Suppress HIV?

Research Questions

Dr. Steve Deeks

Two critical questions for evaluating cure strategies are: First, how does HIV rapidly escape immune control when antiretroviral therapy (ART) is discontinued, even in patients with decades of viral suppression on treatment? Second, are there changes in immune function that occur very soon after stopping ART that could predict viral relapse before virus is detectable in the blood?

Findings

A commentary published in the Journal of Clinical Investigation analyzed a study of 29 HIV-positive individuals from Thailand on long-term ART. All stopped treatment—16 as various scheduled attempts at a cure. The investigators found that the innate immune system, which kicks in prior to recognizing a specific viral invader, acts very strongly and very early after stopping ART. The predominant immune cell involved—the plasmacytoid dendritic cell, or pDC—produced large amounts of an interferon known to block viral growth. That activity was noted before HIV was detectable in the blood. Then, for unknown reasons, the pDCs stopped producing large amounts of interferon and HIV became detectable in the blood. The authors of the commentary added that an increase in CD30+ T cells in the blood could also be a harbinger of a failed HIV cure strategy, prior to finding HIV in the blood.

Impact

The authors conclude: “Perhaps the most important conceptual advance in this study is that careful interrogation of the immune system just as HIV begins to spread after ART [interruption] can provide unique information regarding why the immune system typically fails to control HIV.” It may also serve as a marker for early return of virus after stopping ART, facilitating evaluation of HIV cure strategies without having to wait for virus to become detectable in the blood.

amfAR’s Role

Commentary co-author Dr. Steve Deeks is affiliated with the amfAR Institute for HIV Cure Research.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32338639

Dr. Laurence is amfAR’s senior scientific consultant.

Does ART Adequately Reach Tissue Reservoirs of HIV?

Research Question

A major impediment to an HIV cure is the persistence of cells latently infected with virus. It is possible that the reservoir may expand in tissues if antiretroviral therapy (ART) is not present at sufficient levels to prevent ongoing rounds of viral replication. Existing studies are inconclusive as to whether differences in such drug levels contribute to ongoing HIV growth.

Findings

Tissue samples, including biopsies of small intestines, lymph nodes, and rectum were obtained from 19 HIV-infected individuals on potent ART. Drug concentrations were measured in these tissues as well as in the blood plasma. Highly sensitive assays were used to determine the level of HIV replication in samples. Higher drug concentrations were observed in the rectum and intestines compared with lymph nodes, whereas levels of HIV growth were higher in those people with lower concentrations of ART in the rectum.

Impact

This study adds to existing research indicating that viral growth continues in tissues where ART concentrations are insufficient to contain it. This may contribute to the persistence of HIV reservoirs and viral rebound during analytic treatment interruption.

amfAR’s Role

Scientists at the amfAR Institute for HIV Cure Research were involved in this study.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32045386

Dr. Laurence is amfAR’s senior scientific consultant.

Probing the Provirus

Research Question

It has long been known that effective antiretroviral therapy (ART) has relatively little impact on the reservoir of persistent virus—a major impediment to curing HIV. However, it is possible that the true impact of ART on this persistent reservoir may be masked by differential effects on two forms of provirus, the stretch of viral DNA that inserts into the DNA of infected cells.

Intact provirus found in persistent reservoir serves as an instruction manual for the creation of new virions. If the provirus is defective, it does not provide sufficient instructions to make infectious virus and can be confused with intact provirus, depending on which tests are used to measure proviral DNA.

To understand the actual effects of ART on the reservoir of intact provirus, researchers used the best test to date to differentiate between intact and defective provirus.

Findings

Researchers followed 81 people living with HIV who suppressed their virus using ART, periodically measuring provirus. The impact of ART on intact provirus was most potent during the first seven years of treatment. During this time, the intact provirus decreased significantly when compared to defective provirus. After seven years, the decrease was less marked.

Researchers then studied various other cofactors such as age, race, and gender, including transgender individuals—finding that only CD4 counts were significantly associated with a decrease in intact provirus. Those who began ART when their CD4 counts were relatively high, or had lower levels of intact proviruses from the start, had faster rates of decline of these intact proviruses.

Impact

The decrease in intact provirus could suggest that despite potent ART, the immune system might be able to differentiate between cells infected with intact provirus and those with defective provirus. Documenting how the reservoirs of intact vs. defective proviruses respond differently to ART and assessing a subset of individuals—about nine percent of the population studied—who had very rapid declines in intact proviruses may assist in future cure strategies.

amfAR’s Role

amfAR funds several researchers involved in this study.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/32045386

Dr. Laurence is amfAR’s senior scientific consultant.

Biomarkers May Point to Post-Treatment Control

Research Question

Dr. Mohamed Abdel-Mohsen

Analytic treatment interruption (ATI)—stopping antiretroviral treatment under the supervision of a doctor—is used by HIV researchers to monitor the effectiveness of a curative intervention. Using ATI, researchers have identified a group of rare individuals able to control their virus without resuming treatment—post-treatment controllers (PTCs). Finding biomarkers that can predict post-treatment control without the need for treatment interruption is a priority for the HIV cure field, not least because this could help protect partners from unnecessary exposure to the virus.

Glycans are sugar molecules that attach to proteins and alter the roles they play in processes such as disease progression. For example, the function of antibodies in fighting infections can dramatically change depending on which glycans dot their surface. In this study, researchers ask whether glycans in blood plasma or on antibodies can be used to identify PTCs before they undergo ATI.

Findings

Researchers analyzed blood plasma and antibody glycans from 47 participants enrolled in ATI studies from two geographic locations: Philadelphia and Johannesburg, South Africa. Researchers found 13 distinct types of glycans that predicted prolonged delay to viral rebound, and six that predicted accelerated rebound during ATI.  

Furthermore, because the HIV strains circulating in the U.S. are different than those in South Africa, the researchers’ findings suggest the potential to use these glycan biomarkers throughout the world.

Impact

The authors have found a simple, non-invasive means of predicting which participants might experience a delay to viral rebound in ATI studies. If validated in larger study cohorts, these glycan biomarkers could identify individuals for whom interventions aimed at antiretroviral treatment-free control of HIV might be more successful.

amfAR’s Role

The lead author in this study, Dr. Mohamed Abdel-Mohsen of The Wistar Institute, is funded by amfAR.

Original Article

https://www.ncbi.nlm.nih.gov/pubmed/31972605

Dr. Flores is amfAR’s associate director of research.

New Methods to Reverse HIV Latency

Research Question

HIV persists in a dormant state primarily in T cells expressing surface proteins known as immune checkpoint (IC) molecules. These surface molecules act as brakes that prevent an overly reactive immune response. In the setting of HIV, ICs might also help keep the virus in immune cells in a latent state.

One approach to eliminating latently infected cells in people living with HIV is to activate the latent virus, and thus induce the death of the infected cell. This led the authors to investigate whether blocking IC proteins might serve as just such a potent activator.

Findings

Four prominent IC proteins were identified on T cells in a test-tube model for HIV latency: PD-1, TIM-3, LAG-3, and TIGIT. These same proteins had previously been identified on T cells taken directly from HIV-positive individuals on antiretroviral therapy.

When an artificial stimulus was used to promote T cell growth, antibodies to two T cell surface proteins—PD-1 and CTLA-4—reversed latency. In the absence of an artificial stimulus, a cocktail of antibodies to PD-1, CTLA-4, TIM-3, and TIGIT reversed latency. The potency of this mixture was as high as other previously used latency-reversing agents.

Impact

FDA-approved drugs that interact with PD-1 and CTLA-4 are currently used in the treatment of some types of cancer. Their availability could speed up the time to determine in clinical trials whether the combined IC blocking approach to latency reversal is effective.

According to the authors, immune checkpoint blockade is “an attractive option” to move into the clinic, as both a potential method of reversing the latent state of HIV and a strategy to boost T cell activity against HIV.

amfAR’s Role

amfAR funds several researchers involved in this study.  

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/31988180

Dr. Laurence is amfAR’s senior scientific consultant.