amfAR-Funded Cure Research, 2015-2016
Principal Investigators and Key Personnel
In just the first 18 months of amfAR’s Countdown to a Cure for AIDS initiative, we have supported 139 principal investigators and key personnel in 16 U.S. states and 9 other countries around the world.
Shaping Innate/Adaptive Immune Effector Functions By TLR9 agonist Immunotherapy
One of the prominent strategies being investigated to cure HIV involves “shocking” latently infected cells into producing the virus, which it is hoped will result in the killing of the infected cells. This shock-and-kill approach has been tested in test tubes and in people; both types of investigation have indicated that the immune system may need to be boosted in order to achieve the killing of latently infected cells shocked into producing virus. Dr. Søgaard and colleagues plan to conduct a small clinical trial of a drug belonging to a class called TLR9 agonists. They have preliminary data that this drug not only boosts the ability of the immune system to kill infected cells by enlisting several different immune functions, it may also serve as a “shock” agent. The findings from this trial will provide further information as to the promise and challenges associated with the shock and kill strategy.
Understanding the role of the HIV Envelope in viral persistence and latency
Scientists have identified several subsets of immune cells that likely comprise the latent reservoir of virus that is impervious both to antiretroviral therapy (ART) and the effects of immune system. Less is known about the kinds of HIV viruses that may preferentially infect these cell subsets. Dr. Roche and colleagues plan to characterize the envelope protein − the viral protein that makes initial contact with a cell that is ultimately infected − to determine whether different cell types contain viruses with distinct variations in the envelope protein. Tthe results will provide information as to the kinds of viruses, as described by their envelope proteins, that may emerge and re-seed infection throughout the body if ART is stopped before a person is cured. Because the envelope protein is a primary target of the immune system, this information may provide clues as to the kinds of immune responses that would be required to eliminate HIV.
Impact of everolimus on HIV persistence post kidney or liver transplant
The immune system plays multiple roles in HIV infection: its cells are the targets of infection; its activity is required to kill both the virus as well as infected cells; and its over-activation may contribute to an increase in the number of target cells that can be infected and the size of the persistent reservoir. Dr. Stock and his colleagues are focusing on this last feature of the immune system. They are conducting a clinical trial in which HIV positive patients receiving kidney or liver transplants will add an immune-suppressing drug called everolimus to their regimen. The research team will compare the size of the reservoir in those patients receiving everolimus to those who do not receive it. The findings will directly inform hypotheses concerning the role of over-activation of the immune system in maintaining the persistent HIV reservoir.
CNS as Reservoir for Subtype C HIV-1 Infection
Different subtypes of HIV prevail in different geographic regions. Subtype C, common in Africa, is far more prevalent than subtype B commonly found in the US, Europe and Australia, yet is far less studied. Dr. Wood and colleagues plan to use brain specimens from deceased patients with subtype C virus to study whether this subtype establishes latent reservoirs differently than does subtype B, and how these effects may manifest in the brain, a sanctuary site for HIV that may be very important, but is difficult to examine. They plan to study how much virus is found in the brains of patients whose virus was well controlled by antiretroviral therapy (ART) in the blood, whether the virus is drug-resistant, and which regions of the brain are the most important sites for harboring HIV. These data are important to understand the contribution of HIV in the brain to the ability to re-seed the infection throughout the body when ART is stopped.
Creation of transgenic CCR5 knockout Mauritian cynomolgus macaques
The Berlin patient, the first person clearly documented to have been cured of HIV, received a transplant of stem cells from a donor with a genetic mutation characterized by the lack of a functional CCR5 protein. (amfAR grantee Dr. Nathaniel Landau discovered the critical role of CCR5 in HIV infection in 1996.) Since that time researchers have labored to understand the contribution of each component of that transplant procedure to the Berlin patient’s cure. One challenge has been the lack of an animal model that fully recapitulates this genetic mutation. Dr. Burwitz and his colleagues plan to generate a non-human primate model that would have this genetic mutation. The development of such a model would allow the testing of many hypotheses concerning the Berlin patient’s cure, as well as, for example, gene therapy interventions designed to cure HIV.
Interleukin-21 therapy to reduce HIV persistence
Scientists have long known that HIV infection is associated with a deleterious over-activation of the immune system. More recently, researchers have hypothesized that this over-activation may be a mechanism whereby reservoirs of virus that are impervious to antiretroviral therapy might be established and maintained. Dr. Paiardini and colleagues recently conducted a study in non-human primates in which they administered IL-21, a hormone whose role is to modulate the functioning of the immune system, to determine its ability to normalize the over-activation of the immune system that occurs as a result of HIV infection. That study provided many promising indications that it can. Dr. Paiardini and colleagues now wish to test the hypothesis, using samples taken during the course of that study, that reducing the over-activation of the immune system might also lead to a reduction in the amount of virus found in persistent reservoirs. If so, the results would indicate that reducing immune inflammation may have an important part to play in curing HIV.
Cell-Intrinsic Immune Modulation of HIV Latency
Latent HIV reservoirs that are impervious to antiretroviral therapy (ART) or the immune system are considered the major barrier to curing HIV. The amount of virus in these reservoirs differs between infected people due to a number of factors, including how soon after infection a person starts ART. Dr. Pillai and his colleagues believe they have identified another factor that influences reservoir size, namely the amount of two antivirus factors present inside a person’s cells: p21 and schlafen 11. They will build on their findings by isolating single infected cells and measuring the amount of these two factors present in those cells. They will study the relationship between levels of p21 and schlafen 11 and the amount and degree of latent virus inside those cells. Ultimately, if the two antivirus factors are found to play a role in determining how latent the virus is, this may constitute a pathway for the development of anti-latency drugs.
Molecular characterization of non-induced proviruses
Recent data generated by amfAR ARCHE grantee Dr. Robert Siliciano and his colleagues suggest that one challenge facing the so-called “shock and kill” strategy to cure HIV is the inability of compounds that “shock” to reach all infected cells. This means that even under optimal conditions, latent proviruses inside some infected cells remain latent. Dr. Planelles plans to characterize the differences between viruses than can be induced and those that remain latent. In particular, he will look for interactions between the genetic material of the virus and chemicals in the cell, various combinations of which might act as an on or off switch. Understanding why some viruses remain non-induced will help researchers hone strategies to ensure that all viruses can be induced, thus leading to the elimination of the infected cells.
Epigenetic mechanisms of HIV transcriptional activation
In a small minority of cells, HIV maintains a latent state after it has integrated itself into the infected cell’s DNA. The ability of these latent viruses to be reactivated − so that infected cells can be identified and killed − depends on a number of factors, not all of which are understood. The virus reactivation process starts with changes in interactions between cell proteins and the DNA of the virus. In some cases, proteins may be recruited to the site of the virus, and in other cases proteins may be actively excluded from interacting with the virus. Dr. Bomsztyk and colleagues plan to use new technology they created to characterize the nature of these interactions in the latent state, and the changes that occur when a virus is reactivated. Understanding all of these interactions will help scientists develop drugs that can activate HIV out of latency so that infected cells can be targeted and killed.
Combining romidepsin and 3BNC117 to deplete the HIV-1 reservoir
The major barrier to curing HIV is the existence of reservoirs of virus that persist despite antiretroviral therapy and the immune system. One of the leading strategies being pursued to cure HIV is known as “shock and kill.” The “shock” part of the stragey involves the use of a drug to induce latently infected cells to produce HIV so that the immune system can detect infected cells. The “kill”part involves the killing of infected cells by the immune system, perhaps achieved by boosting the ability of a weakened immune system to do so. In terms of the “shock” part of the strategy, a team of former amfAR grantees in Denmark that includes Dr. Søgaard produced the most promising data to date after using a cancer drug called romidepsin. For the “kill” part of the strategy, Dr. Nussenzweig and colleagues recently published data describing the elimination of infected cells in mice using antibodies including 3BNC117. Dr. Nussenzweig, working with Dr. Søgaard and German colleague Dr. Fätkenheuer now plan to test in infected people the ability of romidepsin combined with 3BNC117 to eliminate infected cells and thus reduce the size of the persistent HIV reservoir. They will be among the first researchers to test a combination cure approach that includes a “shock” and “kill” component in people with HIV.
Combining CTL with TLR-2 Agonists to Eradicate Natural HIV Reservoirs
Several groups of researchers testing the shock and kill strategy for curing HIV have been challenged by the inability of the immune system of patients to kill HIV-infected cells. Preliminary data gathered by Dr. Jones and his colleagues suggest that a drug that acts to increase the activity of a protein known as TLR2 may have an effect on both shock and kill. They plan to test combinations of this TLR2 agonist with a variety of cytolytic (killer) T cells or CTLs, specialized to kill HIV-infected cells. They will investigate whether these combinations can induce latently infected cells to produce virus, and whether the TLR2 agonist can improve the ability of the killer T cells to kill the infected cells. These data will provide insights into what will be needed to make the shock and kill strategy effective in curing HIV.
The size and maintenance of the latent HIV reservoir in T-cell subsets
Memory CD4 T cells are thought to be the main type of cell that harbors latent HIV, in turn the largest barrier to curing HIV. There are several types of memory CD4 T cells, each of which might contribute differently to the reservoir. A recently discovered subset, called Tscm, is the main focus of Dr. Massanella’s planned studies. Several characteristics of these cells, including their ability to produce identical copies of themselves, have led to the hypothesis that they may contribute an ever-increasing proportion of the reservoir over time. Understanding which cells the reservoir hides in, and how the relative contributions of each subset of cells may change over time, will help researchers design interventions specifically targeting the reservoir cells.
Broadly Neutralizing Antibodies for HIV-1 Remission and Eradication
One of the greatest challenges in curing HIV is a small pool of latently infected cells that are difficult to identify and kill specifically while leaving uninfected cells intact. Dr. Barouch and colleagues plan to conduct detailed investigations in the lab, in monkeys and in people, of the ability of combinations of antibodies to specifically kill latently infected cells. Interest in the potential role of antibodies in curing HIV has grown recently due to the discovery of antibodies that are more potent than previous generations, as well as a greater understanding of their role not only in neutralizing viruses but also in targeting infected cells. The team will use two antibodies already shown to be especially potent and will characterize in the lab the complementary ways in which they may identify and kill infected cells. In monkeys, the antibodies will be tested alone and together, in the presence of a newly described drug that can flush or shock the virus out of latently infected cells and may thus aid in the ability of the antibodies to locate infected cells. Finally, the same combination of antibodies and drug will be tested in HIV-infected subjects to determine whether this shock and kill approach may be a viable route to an HIV cure in people.
Impact of Sirolimus (Rapamycin) on HIV-1 Persistence and Immune Function
One of the central features of HIV infection is the disruption of the normal functioning of the immune system, which some researchers believe may also contribute to the ability of the virus to persist even in the face of an immune response. Dr. Henrich and colleagues plan to test the ability of the transplant drug sirolimus to restore to normal many aspects of the dysfunctional immune system in infected people. Because of the complexity of the immune system and the potential effects of sirolimus on its functions, they will first characterize in the lab how the drug may increase the activity of some beneficial components of the immune system while also suppressing the detrimental activity of other components. They will then investigate the effects of sirolimus in a monkey model of HIV infection before moving to the investigation of the effect of the drug on persistent HIV reservoirs in people, using samples from a clinical trial that is already underway as well as from a small study they will conduct themselves. As sirolimus is already approved for use in people, this approach may prove especially promising.
Combination immune checkpoint blocker inhibition to eliminate HIV latency
Although the immune system mounts a vigorous response against HIV and eliminates all but a very small fraction of infected cells, those remaining infected cells prevent an infected person from being able to stop taking antiretroviral therapy and thus constitute a barrier to a cure. One leading theory as to the inability of the immune system to eliminate these last remnants of infected cells concerns immune checkpoints, which refer to a set of mechanisms that limit the duration of an immune system response so that the immune system does not become exhausted and/or start to attack the individual in addition to any disease. Tests of drugs that block these checkpoints in cancer have shown promise, and Dr. Lewin and team plan to determine whether blocking immune checkpoints may also be effective against HIV. They are interested in two such drugs, which they will test alone and together, on healthy immune cells that are infected with HIV in the lab. The two drugs will then be tested alone and together in monkeys, before the group tests the two drugs on blood and tissue samples taken from HIV-infected people. Positive results in these experiments would provide impetus for a clinical trial to test whether immune checkpoint blockers might cure HIV infection.
HIV Cell-to-Cell Transmission and the Establishment of Latency
A major obstacle to HIV eradication is the presence of a reservoir of virus that is established soon after infection. The latent virus is maintained even when antiretroviral therapies prevent detection of virus in the blood. The mechanisms that maintain this reservoir despite many years of antiretroviral therapy are still not fully understood. Dr. Agosto is studying one mechanism that involves the covert shuttling of virus between cells, which perpetuates the viral reservoir and could be an important factor by which the virus evades the immune response.
Identification, reactivation and elimination of latent HIV-1 in humanized mice
The major barrier to curing HIV infection is believed to be a persistent reservoir of virus that is established soon after infection. In subjects whose virus is suppressed by antiretroviral therapy below the limit of detection in blood, the withdrawal of treatment reliably results in viral rebound. Awakening this latent virus with drugs would provide the immune system with an opportunity to kill cells that harbor the reservoir, thereby, eradicating HIV. Dr. Shan has developed a novel mouse model to test these latency reversing drugs and study their ability to reactivate HIV.
Allogeneic Stem Cell Transplant in HIV-1-Infected Individuals (renewal)
The first case of HIV cure occurred in the Berlin patient, who received a stem cells transplant in Germany to treat his cancer, using cells with the CCR5 delta-32 mutation as a way to treat and ultimately cure his HIV infection. Many researchers around the world have tried, so far unsuccessfully, to duplicate this case to test which were the crucial components of the intervention. Because the genetic mutation is most common in Europe, and because various donor screening procedures can be carried out more easily in Europe than in the United States, Drs. Martinez-Picado and Wensing and their colleagues have established a consortium of European researchers who anticipate having several HIV patients in need of stem cell transplants. They will continue their ARCHE work whose aim is to try to replicate the experience of the Berlin patient, and to study differences in the HIV outcomes of patients who undergo similar versus different stem cell transplant procedures. They have already identified 12 HIV patients who have undergone stem cell transplants and continue to follow the 7 who are still alive. This unique consortium presents an opportunity to learn exactly how the cure was achieved in the Berlin patient, and to use this knowledge to build interventions that could be applied more widely.
amfAR Institute for HIV Cure Research
Established with a five-year $20 million grant to the University of California, San Francisco, the amfAR Institute for HIV Cure Research brings together many of the finest minds and most experienced researchers working in the field today. Under the direction of renowned AIDS researcher Dr. Paul Volberding, teams of investigators will work collaboratively to address the scientific challenges that stand in the way of a cure. The Institute is the centerpiece of amfAR’s Countdown to a Cure for AIDS initiative, which aims to develop the scientific basis of a cure for HIV by the end of 2020. The Institute will support teams of scientists working across the research continuum − from basic science to clinical studies − and will tap into UCSF’s extensive research network across the region. It will involve collaborations with the Gladstone Institute of Virology and Immunology (GIVI) and Blood Systems Research Institute, as well as Oregon Health and Science University; University of California, Berkeley; Gilead Sciences; and the Infectious Disease Research Institute in Seattle, Washington.
Tandem latency reversal and suicide prodrugs to eliminate HIV reservoirs
A major obstacle to HIV eradication is the presence of a reservoir of virus established soon after infection. This cryptic reservoir, responsible for viral rebound once the patient is off antiretroviral therapy, is difficult to locate because cells that harbor the virus are indistinguishable from non-infected cells. To compound the problem, the virus itself cripples the immune response that might otherwise be able to kill infected cells. These issues are being circumvented by a bioengineer and polymer chemist, Dr. Zelikin. Dr. Zelikin brings his expertise developing prodrugs, temporarily inactive drugs that become active only in the presence of a specific protein, to eradicate the HIV reservoir. The novel prodrug he will design enters all cells equally, whether HIV infected or not, but lies dormant until HIV is reawakened-it will exert its effect only in cells that are infected with and beginning to produce HIV. Collaborating with Dr.Tolstrup, a virologist and HIV latency expert, Dr. Zelikin will reawaken HIV production by modifying a second drug-a latency reversing agent-that has already shown promise in clinical trials. The modifications proposed will increase the LRA’s potency while decreasing toxicity. After LRA initiates HIV production, the prodrug will be activated, delivering a toxic payload specifically to HIV-infected cells, resulting in their death and thus a reduction, or even elimination, of the reservoir. These two drugs used in tandem are a unique approach that increases specificity and potency of an established cure approach, while minimizing toxic side effects.
Eradicating the HIV reservoir: Using microfluidics to exploit killer T cells
Killer T cells are part of the immune system’s arsenal against virally infected cells. Despite their name, not all members of this group are equally effective in killing HIV infected cells. To date, efforts to isolate killer T cells with the most potent killing potential have been too broad to deliver the results needed to make strides against disease. This problem is being solved by Dr. David Weitz, a physicist and world recognized leader in microfluidics. Dr. Weitz has harnessed his years of cutting edge contributions of applied physics in biology, by developing a machine that uses fluid mechanics to specifically isolate the best, most effective killer T cells from those that are less potent. He proposes to isolate these killers from patient samples, clone them in a petri dish, and use a humanized mouse model to test whether the reinjection of these killer cells can lead to a functional cure of HIV. His collaboration with Dr. Bruce Walker, an HIV pioneer whose studies have defined the field of HIV immunology, will ensure that this novel, microfluidic based approach will test the necessary elements that could lead to T cell therapy in humans.
Optimized assays to measure the latent SIV reservoir in rhesus macaques on ART
Rhesus macaques infected with SIV, the non-human primate equivalent of HIV, are an important research model that have helped to solve some of the most crucial questions in HIV. Until recently, however, due to suboptimal antiretroviral therapy (ART), monkeys on therapy did not routinely achieve suppression of viral replication. This important caveat prevented studies on the viral reservoir, the major obstacle preventing an HIV cure. Recently, however, scientists have developed a new ART regimen to treat monkeys that seems to fully suppress viral replication, similar to what is observed in humans treated successfully with ART. Dr. Maud Mavigner has proposed a comprehensive study to identify the most accurate methods to measure the viral reservoir in this monkey model, comparing cutting-edge techniques against the gold standard. Upon completion, her studies will ready this model for use in curative interventions, thus bringing us one step closer to HIV cure studies in humans.
Mechanisms and correlates of post-ART treatment control in SIV-infected macaques
In the majority of HIV infected persons, infection resumes once antiretroviral therapy has stopped because the body’s defense system is unable to control the virus. A small number of patients, such as the VISCONTI cohort, who stopped therapy after several years did not experience classical viral rebound to high levels but rather were able to control the virus to very low levels. It is not known how these “post-treatment controllers” are able to lock down HIV and it is an active area of investigation. Dr. Mirko Paiardini has recently described a non-human primate model of post treatment control and an association between levels of IL-10, a key anti-inflammatory protein, and a cell subset recently discovered to be a reservoir of HIV, T follicular helper cells (Tfh cells). Dr. Paiardini will pursue these findings to investigate the mechanisms through which IL-10 maintains the reservoir in Tfh cells and whether it can predict the rare predisposition to ‘post-treatment control’. The goal is to harness these immune factors to exploit for use in humans.
Genomic locations of HIV proviruses responsive to latency reversing agents
HIV is able to establish a cryptic viral reservoir because it inserts its genes directly into our DNA. The particular region of human DNA that the virus inserts itself into can help determine whether the virus is an active reproducer or remains latent. Researchers are developing drugs to reverse latency, but not all inserted viruses are reawakened at the same time or with the same drug. Dr. Beliakova-Bethell seeks to study how the genes surrounding the newly inserted HIV dictate how it responds to the drugs meant to reawaken it and whether these effects might vary across types of infected cells. The results of these studies will be important as we develop new drugs to target this dormant viral reservoir and could redesign our approach to latency reactivation.
Hormonal control of latent HIV proviruses
Reawakening the latent viral reservoir, the main obstacle preventing eradication of HIV, is an area of active research. Finding drugs that can enhance the activity of latency reversing agents (LRAs) would accelerate the progress toward a cure. To that end, Dr. Jonathan Karn has found that estrogen can significantly affect the degree of viral latency. Now, Dr. Karn proposes to embark on exploratory studies to determine whether other hormone classes have similar effects. His work could expedite cure studies by providing current clinical studies with ready to-go, FDA approved drug classes that would improve the efficacy of the “shock” arm of the “shock and kill” cure strategy.
Development of a humanized superagonist antibody to human IL-21 for HIV cure
Recent amfAR-funded work indicated that the immune hormone IL-21 can reduce ongoing inflammation − importantly, this effect was pronounced in gut tissues where ongoing immune inflammation is associated with adverse clinical consequences such as cardiovascular disease, cognitive disease, and kidney and bone abnormalities - and reduce the viral reservoir size in monkeys. IL-21 is already showing promise in clinical trials in humans for the treatment of a variety of cancers, by increasing the ability of the immune system to kill its targets and to generate antibodies. However, IL-21 has some potential drawbacks, including its relatively short life-span in the blood and the need to increase the dose to potentially toxic levels in order to maximize its efficacy. Dr. Yu plans to lead a team of researchers to develop and test the ability of an antibody, called a superagonist, to increase the effectiveness of IL-21 by lowering the required doses and increasing the time that IL-21 is present in the body before being degraded. They will test a battery of potential superagonists to find the most promising candidates, which will then be tested on patient cells in a test tube. This workplan represents the initial phase of a long-term plan to test the superagonist in animal models to prepare for testing in patients.
Uncovering HIV-1-infected cells: a new path towards a cure
A major obstacle to HIV eradication is the presence of a reservoir of virus that is established soon after infection and lies dormant during effective antiretroviral therapy. One proposed approach to curing HIV uses drugs to force the virus to reproduce itself. During this process, copies of the viral protein Env are placed on the surface of the infected cells. Env would normally interact with the human protein CD4, also on the cell surface, and this interaction would expose the infected cell to attack by antibodies. To protect itself from this possibility, HIV removes CD4 from the cell surface during its initial infection of the cell. Dr. Andrés Finzi has proposed a strategy that replaces CD4 with a replica. He will use cells from patients with latent virus to determine if the addition of this CD4-replica, along with drugs to reawaken HIV, can effectively kill the HIV reservoir through an antibody-mediated attack. His intention is that the CD4-replica will be used as part of a larger ˜shock and kill’ strategy aimed at curing HIV.
Discovery of Tools to Modify the Fate of Uracilated HIV DNA in Macrophages
HIV is difficult to eradicate because it inserts itself directly into our own DNA. However, before insertion, it must first convert its genes into an acceptable, insert-ready form. Typically, in the majority of cells that HIV infects, the conversion process makes HIV genes indistinguishable from our own DNA. However, in a particular type of cell, a macrophage, the nascent HIV DNA can incorporate incorrect building blocks and the resulting viral DNA is scattered with errors. The outcome can include: 1) elimination of the HIV, 2) a version of viral DNA that is more prone to dormancy, or 3) an active infection. Dr. James Stivers is proposing to characterize the events that lead to the three outcomes. His work will bring new information on how the viral reservoir, the critical obstacle to HIV eradication, is established and maintained in the small fraction of the reservoir that is not in T cells.
Quantitative HIV reservoir assay using bar-coded RNA
Eradicating the HIV reservoir is a major focus of cure efforts. Thus, the goal of most curative interventions is to reduce the size of the reservoir, which is measured by determining the number of cells harboring infectious virus. To date, the gold standard to record such measures has been expensive and requires huge volumes of blood which can be taxing on patients. Dr. Jonathan Karn proposes to use an improved method that reduces the need for burdensome blood draws and can be performed in a large number of patients per experiment. He will compare his new methodology to several established methods to ensure it is both accurate as well as cost- and time-efficient. The new assay can then be used to, for example, identify new latency reversing drugs or determine whether a drug intervention has reduced the size of the reservoir in a clinical trial.
Development of a humanized superagonist antibody to human IL-21 for HIV cure
Recent amfAR-funded work indicated that the immune hormone IL-21 can reduce ongoing inflammation − importantly, this effect was pronounced in gut tissues where ongoing immune inflammation is associated with adverse clinical consequences such as cardiovascular disease, cognitive disease, and kidney and bone abnormalities − and reduce the viral reservoir size in monkeys. IL-21 is already showing promise in clinical trials in humans for the treatment of a variety of cancers, by increasing the ability of the immune system to kill its targets and to generate antibodies. However, IL-21 has some potential drawbacks, including its relatively short life-span in the blood and the need to increase the dose to potentially toxic levels in order to maximize its efficacy. Dr. Yu plans to lead a team of researchers to develop and test the ability of an antibody, called a superagonist, to increase the effectiveness of IL-21 by lowering the required doses and increasing the time that IL-21 is present in the body before being degraded. They will test a battery of potential superagonists to find the most promising candidates, which will then be tested on patient cells in a test tube. This workplan represents the initial phase of a long-term plan to test the superagonist in animal models to prepare for testing in patients.
Analytic Treatment Interruption to Study Viral Reservoirs and as Test for Cure in HIV-infected Adults on ART
The treatment of HIV-infected persons with antiretroviral therapy (ART) has been so effective that most patients on ART experience a reduction of their viral load to below the limit of detection. Suppression of the virus, however, is dependent on ART because if stopped, the virus quickly returns. The rebound is due to the presence of a persistent viral reservoir that is established soon after infection. It is thought that the longer an HIV infection goes untreated, the larger the reservoir and the more difficult it becomes to rid the body of HIV. Conversely, if the virus is identified and treatment initiated soon after infection, a smaller reservoir is established that may be easier to eradicate. However, identifying patients soon after infection is difficult unless their HIV status is being constantly monitored. Dr. Steven Deeks has found a way around this problem by identifying clients at PrEP (pre-exposure prophylaxis) clinics, which offer ART to uninfected persons at risk of acquiring HIV. As part of their pre-initiation of therapy, these clients’ HIV status is closely monitored. Through the PrEP clinic structure, Dr. Deeks has identified individuals who became HIV positive during the pre-initiation phase and have started therapy, sometimes even before symptoms occur. By temporarily pausing their ART, he plans to determine whether initiation of ART soon after infection leads to remission, and possibly cure.
Predictors of time to viremia with an analytic treatment interruption
One of the greatest challenges in HIV cure research is how to establish whether a person has been cured. This issue must be solved before the results of clinical trials testing various methods to cure HIV can be compared. Currently, the most definitive method involves taking the subject off antiretroviral therapy (ART) and determining whether virus grows − rebounds - in the blood, indicating that replication-competent virus remains in the person’s body, and how long this takes. Virus rebound may take weeks to months, however, or even years, as was the case in the Mississippi child. The longer the rebound takes, the closer the intervention is likely to have come to curing the patient. While waiting to see if the virus starts to grow, blood must be drawn frequently and tested for the presence of the virus, which is both expensive as well as time-consuming and arduous for the patient. Ideally, scientists should be able to measure something in the blood or tissues that will describe whether a patient is cured, without having to take the patient off ART. Drs. Schacker and Deeks plan to lead a study to discover such a measure. They will enroll patients on ART and take samples of their blood and tissues before taking them off ART. During the period of waiting for virus rebound, multiple blood samples will be taken and tested for the presence of the virus. Once the virus becomes detectable in the blood, the patient will re-start ART, and intensive blood and tissue sampling will be performed again. The researchers will look for measures in the blood and tissues that predict a longer delay to rebound. They will investigate the effects on delay to rebound of the extent to which virus is actively replicating, the size of the reservoir and gender as just some of many measures. Understanding which measures in blood or tissues predict a longer delay to rebound will help researchers design the right measures to predict the efficacy of cure interventions in future studies.
Targeting engineered nanoparticles for therapeutic purge of HIV-1 reservoir
Locating the viral reservoir − HIV-infected latent T cells − has eluded scientists because the sanctuaries in which it hides are spread throughout the human body and latently infected cells are difficult to distinguish from healthy cells. Certain cells of the immune system, such as dendritic cells, however, can naturally seek out and interact with T cells throughout the body. Dr. Nuria Izquierdo-Useros has been funded to utilize these dendritic cells as Trojan horses to deliver a toxic blow to the reservoir.
Specifically, Dr. Izqueirdo-Useros developed special compounds called nanoliposomes, or small cell-like bubbles, to deliver drugs to HIV-infected CD4 T cells as well as to CD8 killer T cells using dendritic cells as the carrier. Capitalizing on the close contact between dendritic cells and both T cell types, the research team will use the compounds to reactivate the viral reservoir in CD4 T cells, jump-start an immune response by killer CD8 T cells, and protect uninfected CD4 T cells from further infection—a “shock, kill, protect” approach.