AIDS Grants Target HIV Persistence
By Bio-IT World Staff
June 3, 2016 | amfAR, The Foundation for AIDS Research, has awarded seven scientists a total of approximately $1.4 million in research grants to better understand why HIV persists in the body despite effective antiretroviral therapy (ART) and pursue novel pathways to a cure. This round of grants was supported in part by the Foundation for AIDS and Immune Research (FAIR).
While ART can successfully suppress HIV to nearly undetectable levels, once treatment stops, the virus quickly rebounds due to the presence of a persistent viral reservoir that remains dormant in the body. It is this reservoir that presents the biggest obstacle to a cure.
“As we continue to build the science around a cure, these research projects will fill some critical gaps in knowledge about the persistence of viral reservoirs, and will undoubtedly inform future clinical studies aimed at finding a cure for HIV,” said amfAR CEO Kevin Robert Frost in a press release.
The new grants are the latest to be awarded under amfAR’s $100 million Countdown to a Cure for AIDS initiative, which is aimed at developing the scientific basis for a cure by 2020. Each grantee will each receive up to $200,000 over two years to test novel research ideas supported by limited preliminary data.
“As we sharpen our focus on finding a cure for HIV, supporting new lines of inquiry remains a vital part of amfAR’s overall strategy,” said amfAR Vice President and Director of Research Dr. Rowena Johnston in the same statement. “The approaches our new grantees are using to crack some of the most challenging questions in cure research today truly deserve the moniker, Innovation.”
The following is a full list of Innovation grant recipients:
Celsa Spina, Ph.D.
University of California, San Diego
San Diego, CA
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 into can help determine whether the virus actively replicates or remains latent. Researchers are developing drugs to reverse latency with the hopes that they will identify infected cells, 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 the response to the drugs meant to reawaken it and whether these effects might vary across infected cell types. The results of these studies will be important as we develop new drugs to target this viral reservoir and could help researchers improve their approach to latency reactivation.
Andrés Finzi, Ph.D.
Université de Montréal, Centre de Recherche du CHUM
Uncovering HIV-1 infected cells: a new path towards a cure
One proposed approach to curing HIV uses drugs to force virus in the persistent viral reservoir to reproduce. 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.
Jonathan Karn, Ph.D.
Hormonal control of latent HIV proviruses
Finding currently approved drugs that can enhance the activity of latency reversing agents (LRAs) would accelerate 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.
Jonathan Karn, Ph.D.
Quantitative HIV reservoir assay using bar-coded RNA
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 greatly increases the number of patients that can be tested at one time. He will compare his new methodology to several established methods to ensure it is both accurate and cost- and time-efficient. The new assay can then be used to identify new latency reversing drugs, for example, or determine whether a drug intervention has reduced the size of the reservoir in a clinical trial.
Maud Mavigner, Ph.D.
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 has 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. 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.
Mirko Paiardini, Ph.D.
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.
James Stivers, Ph.D.
Johns Hopkins University
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 is established and maintained in the small fraction of the reservoir that is not in T cells.