Four teams of leading scientists receive amfAR funding in collaborative effort to pursue HIV/AIDS eradication
The principal barrier to curing HIV is the reservoirs of infected cells that cannot be cleared by the immune system. Adding to the multiple ways HIV shields itself from attack is the recent discovery of an “invisibility cloak.” But what if we could uncloak the virus so that it can be seen and targeted by the immune system? That’s the task that researchers Jane Rasaiyaah and Leo James have set for themselves in a research project being supported in a new round of cure-focused research funding from amfAR.
The new grants, totaling more than $703,000, will support the work of four teams of scientists working within the amfAR Research Consortium on HIV Eradication (ARCHE), an initiative launched in 2010 to exploring potential strategies for eliminating HIV infection. This brings amfAR’s investment in cure-focused research to almost $4 million in the last six months alone.
One strategy scientists are exploring to cure HIV is known as “shock and kill,” which would use drugs to “shock” the latent virus into replicating. Once active, the infected cells would then be “killed” by the immune system and antiretroviral drugs. In an effort to boost the effectiveness of the immune system, Drs. Rasaiyaah and James, working at University College London in the United Kingdom, plan to build on the newly characterized “invisibility cloak” in HIV-infected myeloid cells. They aim to determine whether a similar mechanism is also at work in T cells and to investigate whether a compound called SmBz can help in uncloaking the virus.
“The work we’re funding through ARCHE is expanding our collective knowledge of HIV and its potential vulnerabilities,” said amfAR CEO Kevin Robert Frost. “It’s very rewarding to see amfAR’s research model allow scientists working in different fields and various parts of the world to capitalize on the most recent findings in our quest for a cure.”
Other teams of researchers funded in this round of ARCHE grants will: study how a type of cells called microglia may form reservoirs of persistent virus in the brain; determine whether the decline of HIV in various T-cell subsets, as well as which subsets the virus persists in, depends on how early antiretroviral therapy is initiated; and develop a technology to visualize whether latent cells have been infected with HIV.
“These new projects will contribute vital new findings to HIV cure research,” said Dr. Rowena Johnston, amfAR vice president and director of research. “The ARCHE program is unlike any other, and we remain confident that this collaborative approach will continue to accelerate the search for a cure that can ultimately be delivered to the 35 million people who need it.”
ARCHE-funded research teams and their projects are as follows:
Paula Cannon, Ph.D.
University of Southern California, Los Angeles, CA
$180,000
Microglia and HIV-1 latency: HIV can persist despite antiretroviral therapy (ART) in various types of immune cells and/or in anatomical niches. The brain may be a particularly important niche because ART may not penetrate sufficiently to suppress the virus, and because the infected cells in the brain – microglia – differ from the main reservoir in the body, comprised of T cells. Dr. Cannon, working with Dr. Jonathan Karn of Case Western Reserve University in Cleveland, will use genetically engineered mice to investigate the ability of microglia to form reservoirs in the brain. They will also interrogate the mechanisms whereby the virus persists in these cells. Understanding reservoirs in the brain will be important to devising a cure that can clear virus from the entire body.
Ann Chahroudi, M.D., Ph.D.
Emory University, Atlanta, GA
$180,000
Defining SIV reservoir kinetics in rhesus macaques: Because ART is unable to clear all HIV, it is important to understand which parts of the body are populated with the virus after maximal viral suppression has been achieved. Dr. Chahroudi will work with Dr. Una O’Doherty of the University of Pennsylvania to study the decline of the virus in various T cell subsets, as well as which subsets the virus persists in, after maximal suppression has been reached, in a monkey model of HIV infection. They hypothesize that when ART is initiated early enough in infection, before peak virus levels are reached (which occurs at roughly day 10-14 after infection), the amount of virus that persists, or the types of cells it persists in, is different than when ART is initiated later. They will be able to sample tissues that are not accessible in humans, and will thus learn more about the potential impact of very early vs. delayed initiation of ART on the ability to cure HIV infection.
Benjamin K. Chen, M.D., Ph.D.
Mount Sinai School of Medicine, New York, NY
$180,000
Harnessing induced hematopoietic stem cells to identify HIV reservoirs: The major barrier to curing HIV is the persistence of infected cells that are not cleared by ART or the immune system. These infected cells are difficult to identify, as they do not differ from uninfected cells in any way that can be detected. In order to facilitate the identification of infected cells, and thus study what makes these persistent, infected cells different from uninfected cells, Dr. Chen will work with Dr. Martin Markowitz of the Aaron Diamond AIDS Research Center to generate a mouse model of HIV infection in which the mice are populated with human cells that are genetically modified to display a signal when they have been infected with HIV. This will enable the isolation and study of those cells that become persistently infected, which may yield clues as to how they can be cleared to achieve a cure of HIV.
Jane Rasaiyaah, Ph.D.
University College London, London, United Kingdom
$163,704
Triggering Innate Immune Responses in HIV Eradication Therapy: One way researchers are trying to cure HIV is by “shocking” the virus out of persistently infected cells, and then “killing” the infected cells so they cannot produce any more viruses. Trials so far have yielded only moderately promising results. Dr. Rasaiyaah, working with Dr. Leo James of Cambridge University, hypothesizes that the success of these kinds of interventions might be increased by boosting the ability of the immune system to detect and kill infected cells. Specifically, they are furthering work by their colleague Dr. Greg Towers who recently published findings indicating that in one subset of infected cells, myeloid cells, the virus is able to hide itself from the immune system and thus escape detection and killing. This team will investigate whether the same holds true for T cells, the main reservoir of HIV, and whether a compound called SmBz, that blocks the human protein that the virus uses to hide itself, can uncloak the virus, reveal it to the immune system, and increase the effectiveness of the “shock and kill” strategy to cure HIV.