New amfAR Grants Spur Innovative HIV Cure Research Collaborations

NEW YORK, Jan. 25, 2016 --- In a move that adds extraordinary new dimensions to the field of HIV cure research, amfAR, The Foundation for AIDS Research, has recruited the expertise of a world-renowned physicist and a leading polymer chemist. The Foundation has awarded $1 million each over four years to Harvard physicist Dr. David Weitz and bioengineer and polymer scientist Dr. Alexander Zelikin of Aarhus University in Denmark. The two will bring their expertise to bear in the effort to eradicate the viral reservoir that is considered the principal barrier to curing HIV. 

The new awards are the latest to be funded by amfAR through its $100 million Countdown to a Cure for AIDS initiative, whose goal is to develop the scientific basis for a cure by 2020. The grants were aimed specifically at recruiting the expertise of scientists working outside the field of HIV in areas that could directly inform efforts to cure HIV. Drs. Weitz and Zelikin will collaborate with leading AIDS researchers Dr. Bruce Walker at Harvard and Dr. Martin Tolstrup at Aarhus University, respectively. 

“Research to find a cure for AIDS has evolved from a process of discovery to a challenge of technology,” said amfAR Chief Executive Officer Kevin Robert Frost. “And recent technological advances have brought with them some exciting opportunities for the cross-pollination of ideas and for adapting cutting-edge technologies to the field of HIV cure research.”

Dr. Weitz, who is the Mallinckrodt Professor of Physics and Applied Physics at the John A. Paulson School of Engineering and Applied Sciences at Harvard University, is a world leader in the field of microfluidics. This cutting-edge scientific field, which involves the manipulation of minuscule volumes of fluid using state-of-the art devices and processes, has already revolutionized a wide array of scientific fields. 

Dr. Weitz has developed a technique that uses fluid mechanics to specifically isolate the most effective killer T cells from those that are less potent. He proposes to isolate these cells—a critical weapon of the immune system against virally infected cells—from patient samples, clone them in a petri dish, and use a mouse model to test whether the reinjection of these killer cells can lead to a functional cure of HIV.  

Dr. Zelikin is an expert in prodrugs—temporarily inactive drugs that become active only when instructed by a second stimulus—which he plans to use to eliminate the HIV reservoir. The project will design a two-component cocktail. One prodrug will be developed to gently reawaken the latent HIV using a drug that Dr. Martin Tolstrup, a virologist and HIV expert, has shown to be effective in patients.  The second prodrug will be designed to specifically initiate the killing of virally infected cells.  Acting in tandem, the two prodrugs administered together are poised to specifically activate the latent viral reservoir and kill the cells harboring HIV.

“The ‘outside the box’ approaches proposed by Drs. Weitz and Zelikin will both expand and invigorate the field of HIV cure research,” said Rowena Johnston, Ph.D., amfAR Vice President and director of research. “We are tremendously excited to be supporting these studies, each of which holds enormous potential for depleting, and perhaps even clearing, the persistent reservoir of HIV.”

Investment Grants 2016  

PI: David Weitz, PhD
Collaborating HIV Scientist: Bruce Walker, MD
Harvard University
$977,114
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.

PI: Alexander Zelikin, PhD
Collaborating HIV Scientist: Martin Tolstrup, PhD
Aarhus University, Aarhus, Denmark
$962,510
Tandem latency reversal and suicide prodrugs to eliminate HIV reservoirs
A major obstacle to HIV eradication is the presence of a latent viral reservoir that is established soon after infection. This cryptic reservoir, responsible for the viral rebound once the patient is off antiretroviral therapy, is difficult to locate and the body’s immune system is unable to clear the viral reservoir. An approach to circumvent these issues is offered here by a bioengineer and polymer chemist, Dr. Alexander Zelikin. The project builds on Dr. Zelikin’s expertise in developing prodrugs—labile drugs that become active when instructed by a specific stimulus. The project will design a two-component cocktail. One prodrug will be developed to gently reawaken the latent HIV using a drug that Dr. Martin Tolstrup, a virologist and HIV expert, has shown to be effective in patients.  The second prodrug will be designed to specifically initiate the killing of virally infected cells.  Acting in tandem, the two prodrugs administered together are poised to activate the latent viral reservoir and kill the cells harboring HIV.

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 the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested $450 million in its programs and has awarded grants to more than 3,300 research teams worldwide. Learn more about amfAR at www.amfar.org.

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Reducing Viral Reservoirs with Immune-Based Therapy

Dr. Mirko Paiardini

Most animal and test-tube models for eliminating latent reservoirs of HIV—the major impediment to an HIV cure—suggest that a pharmacologic approach combining antiretroviral therapy (ART) and inducers of the latent virus alone will not be sufficient to completely eradicate HIV. An infected person’s immune system must also be enticed to play an active role in the effort to eliminate the T cells harboring dormant virus.

Writing in the December issue of the Journal of Clinical Investigation, amfAR grantee Dr. Mirko Paiardini from Emory University, along with amfAR-funded scientists Drs. Remi Fromentin, Ann Chahroudi, Christian Apetrei, Nicolas Chomont, Guido Silvestri, and others from Emory University, University of Montreal, University of Pittsburgh, Case Western Reserve, and the Frederick National Laboratory for Cancer Research, report on findings in an exciting new monkey model that may help accomplish this goal.

The researchers sought to quench the HIV-related immune inflammation that continues despite the reduction of HIV levels to undetectable by ART. Such inflammation not only leads to accelerated kidney, heart, and bone disease, but also appears to help maintain the viral reservoirs that persist even after long-term ART. The team postulated that defects in gut immunity found in people living with HIV that cause the release of intestinal microbes into the blood, and perhaps other associated factors, were a major impetus for perpetuating this inflammation, and were therefore a promising target for new treatments.

The scientists used a modified version of a natural immune hormone, IL-21, which is currently undergoing clinical trials to treat advanced cancers. IL-21 is able to restore the number and function of a specialized type of CD4+ helper T cell in the gut, the Th17 cell. HIV infection causes loss of these cells, which hampers gut immunity. In the study, 16 rhesus macaques were infected with SIV, the simian equivalent of HIV. Two months later, all animals were started on a potent five-drug ART regimen. Half of these animals were also given two cycles of six weekly doses of IL-21, injected under the skin. Four additional weekly doses were administered after ART was stopped.

Paiardini and colleagues found that not only were Th17 cells restored and the markers of immune activation decreased in the blood and intestines in the animals receiving IL-21, but the levels of circulating SIV and latent virus were also lower compared with the control animals. These effects were maintained for the entire eight months the animals were observed off ART.

Although the exact mechanisms behind these IL-21 effects remain to be documented, these promising monkey results suggest an important role for IL-21 in clinical trials of HIV eradication.

Cure Matters: Conversations with Leading HIV Researchers

Cure Matters: Conversations with Leading HIV Researchers

Published Friday, September 18, 2015

What cure-focused projects are the world’s foremost AIDS researchers working on? What are the most promising recent developments in the field of cure research? And how close are we to finding a cure? In a series of interviews at the International AIDS Society conference in Vancouver this summer, amfAR put these and other questions to several current grantees.

Dr. Benjamin Burwitz of Oregon Health and Science University, Portland, is trying to determine the mechanism of action that led to the first and only known HIV cure in "the Berlin patient" by attempting to recreate the case in nonhuman primates. 

Dr. Paula Cannon of the University of Southern California, Los Angeles, is attempting to engineer HIV-proof immune cells, as well as investigating latent reservoirs in the brain. 

Dr. Ann Chahroudi of Emory University School of Medicine and Yerkes National Primate Research Center, Georgia, is using nonhuman primate models to evaluate HIV reservoir persistence.

Dr. Timothy Henrich of the University of California, San Francisco, is investigating new drugs aimed at boosting the immune system’s ability to clear the body of HIV.

Dr. Brad Jones of George Washington University, Washington, D.C., is focusing on a specific drug that both reactivates latent HIV and enhances the immune system’s ability to kill infected cells.

Dr. Marta Massanella of the University of California, San Diego, is studying a recently discovered subset of CD4 T cells believed to contribute heavily to the latent HIV reservoir.

Dr. Satish Pillai of Blood Systems Research Institute and University of California, San Francisco, is studying natural factors that affect the size of the latent HIV reservoir.

Meet the Cure Council

Research supported and driven by the Countdown to a Cure initiative will be guided by a group of eminent scientists who make up the Cure Council.

David Baltimore, Ph.D.
Professor of Biology, California Institute of Technology

In 1975, at the age of 37, Dr. Baltimore shared the Nobel Prize for Physiology or Medicine with Howard Temin and Renato Dulbecco. The citation reads, "for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell." At the time, Dr. Baltimore's greatest contribution to virology was his discovery of reverse transcriptase, which is essential for the reproduction of retroviruses such as HIV.

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Françoise Barré-Sinoussi, Ph.D.
Director of the Regulation of Retroviral Infections Division (Unité de Régulation des Infections Rétrovirales), Institut Pasteur, Paris, France

In 2008, Dr. Barré-Sinoussi was awarded the Nobel Prize in Physiology or Medicine, together with her former mentor, Luc Montagnier, for their discovery of HIV. She served as president of the International AIDS Society from 2012 to 2014 and is chair of the Towards an HIV Cure project, an initiative of the International AIDS Society.

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Myron (Mike) Cohen, M.D.
Associate Vice Chancellor for Global Health; J. Herbert Bate Distinguished Professor of Medicine, Microbiology and Immunology, and Public Health; Director, Institute for Global Health and Infectious Diseases; Chief, Division of Infectious Diseases; Director, Center for Infectious Diseases at University of North Carolina

The author of more than 500 publications, Dr. Cohen has written extensively about the prevention of HIV infection. The HIV Prevention Trials Network 052 study (HPTN 052), led by Dr. Cohen, was named the 2011 Breakthrough of the Year by the journal Science. The study demonstrated that treating HIV-positive people early can lead to a 96% reduction in HIV transmission to their sex partners.

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Beatrice Hahn, M.D.
Professor of Medicine, Perelman School of Medicine, University of Pennsylvania

In 2002, Discover magazine named Dr. Hahn one of “The 50 Most Important Women in Science.” Her laboratory has had a longstanding interest in elucidating the origins and evolution of human and simian immunodeficiency viruses, and in studying HIV/SIV gene function and disease mechanisms from an evolutionary perspective. She is recognized for deciphering the primate origins of human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2).

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Richard Jefferys
Basic Science, Vaccines, and Cure Project Coordinator at Treatment Action Group (TAG)

A highly respected voice in AIDS research, Richard Jefferys has more than 20 years experience in the field of HIV treatment access, clinical trials, and vaccine and cure research. Since joining the Treatment Action Group in late 2001, Richard has worked for TAG’s Michael Palm Basic Science, Vaccines, and Cure Project. He also writes on the pathogenesis and immunology of HIV infection for a range of publications.

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Carl June, M.D.
Professor in Immunology, Perelman School of Medicine, University of Pennsylvania

Dr. June’s pioneering research involves immunotherapy for cancer, chronic infections and HIV. Using gene therapy and stem cell transplantation in cancer, specifically chronic lymphocytic leukemia and acute lymphoblastic leukemia, Dr. June has treated cancers that were previously unresponsive to treatment. In September 2011, The New York Times described his work as “a turning point in the long struggle to develop effective gene therapies against cancer.”

amfAR Establishes San Francisco-Based Institute for HIV Cure Research

amfAR Establishes San Francisco-Based Institute for HIV Cure Research

Institute will foster innovation among collaborative research teams,
with the goal of developing the scientific basis for a cure by 2020

NEW YORK, November 30, 2015 – amfAR, The Foundation for AIDS Research, today announced the establishment of the amfAR Institute for HIV Cure Research, an innovative collaborative enterprise based at the University of California, San Francisco (UCSF). As the cornerstone of amfAR’s $100 million cure research investment strategy, the aim of the Institute will be 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.

“We intend to quicken the pace of cure research by supporting a collaborative community of leading HIV researchers in one cohesive enterprise,” said amfAR Chief Executive Officer Kevin Robert Frost. “The institute will allow them to conduct the science, share ideas, and test and evaluate new technologies and potential therapies in a state-of-the-art environment. And I can think of no better base for such an enterprise than the San Francisco Bay Area, the crucible of technological innovation in America.”

UCSF and amfAR - U.S. Representative Nancy Pelosi

“Furthermore, establishing an institute dedicated to finding a cure for HIV in a city that was once considered ground zero of the AIDS epidemic brings full circle the outstanding work that UCSF’s researchers have been doing over the past 30 years,” added Frost.

Worldwide, it is estimated that nearly 37 million people are infected with HIV. Current antiretroviral therapy (ART) can help people with HIV live longer and healthier lives, but it cannot eliminate the virus.  There is general consensus among the scientific community that the principal barrier to a cure is the reservoirs, or pockets, of virus that remain in a person even after they have reached “undetectable” levels of HIV as a result of ART.    

The new Institute, headquartered in UCSF’s Global Health and Clinical Sciences Building at Mission Bay, was established with a $20 million grant over five years. It will enable teams of researchers to work collaboratively, across institutions and across disciplines, to address the four key challenges that must be overcome to effect a cure: pinpoint the precise locations of the latent reservoirs of virus; determine how they are formed and persist; quantify the amount of virus in them; and finally, eradicate the reservoirs from the body.

“For those of us who watched helplessly as thousands died, the opportunity to try to develop an HIV cure is truly amazing,” said Paul Volberding, M.D., a UCSF Professor of Medicine who will direct the new amfAR Institute. “We are proud to have been chosen by amfAR as the only amfAR HIV Cure Institute in the nation. We’re ready to end this epidemic.”

 “The San Francisco area has a higher concentration of scientific thought leaders in HIV than anywhere else in the world,” said amfAR Vice President and Director of Research Dr. Rowena Johnston. “The Bay Area has consistently led the way in developing and implementing scientific advances in HIV prevention and treatment, and the potential for this team of researchers to develop a cure is unparalleled.”

Joining Dr. Volberding on the leadership team will be Mike McCune, M.D., Ph.D., Chief and Professor, Division of Experimental Medicine, UCSF; Warner Greene, M.D., Ph.D., Director and Nick and Sue Hellmann Distinguished Professor of Translational Medicine, Gladstone Institute of Virology and Immunology, Professor of Medicine, Microbiology and Immunology, UCSF, and Co-Director, UCSF-Gladstone Center for AIDS Research; Satish Pillai, Ph.D., Associate Professor of Laboratory Medicine, UCSF, and Associate Investigator, Blood Systems Research Institute; Steven Deeks, M.D., Professor of Medicine, UCSF; Teri Liegler, Ph.D., Director of the Virology Core Laboratory at UCSF-GIVI Center for AIDS Research; andPeter Hunt, M.D., Associate Professor of Medicine in the HIV/AIDS division and a member of the Executive Committee of the AIDS Research Institute at UCSF. They will work in collaboration with Afam Okoye, Ph.D., staff scientist at Oregon Health & Science University.

“This exciting new initiative will bring together the scientific, technological and team-building expertise of amfAR and its Institute partners,” said Dr. Johnston. “We are confident that this new combination approach will enable us to rapidly advance the science around a cure for HIV.”

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 the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested $415 million in its programs and has awarded grants to more than 3,300 research teams worldwide.

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A Prominent Role for Innate Immunity in Eradicating HIV

Dr. Mathias Lichterfeld

Most animal and test tube models for elimination of latent HIV infection—the major impediment to a cure—suggest that a pharmacologic approach alone will not be sufficient. An HIV-positive person’s immune system must be stimulated to play an active role in efforts to eliminate T cells harboring dormant virus. Writing in the October issue of the Journal of Virology, amfAR-funded scientists Drs. Mathias Lichterfeld of Massachusetts General Hospital (MGH); Lars Østergaard and Ole Søgaard of Aarhus University, Demark; and Sarah Palmer of the University of Sydney, Australia; along with associates from the Ragon Institute of MGH, MIT, and Harvard, and the Frederick National Laboratory for Cancer Research; provide new insights into how this might be accomplished.

The international team of researchers analyzed immune factors associated with changes in levels of proviral HIV DNA—one measure of HIV persistence—in 15 HIV-positive individuals receiving antiretroviral therapy in addition to panobinostat, a drug capable of activating latent virus. Surprisingly, the levels and potency of a key component of anti-HIV immunity, the CD8+ killer T cell, bore no relationship to changes in HIV DNA during panobinostat treatment. But changes in a critical component of our innate immune system, the natural killer (NK) cell, did relate.

A natural killer cell (Photo: David Scharf)

The proportion of total NK cells and one of its major subsets was inversely linked to HIV DNA levels throughout the course of treatment. And a second NK cell subset was specifically altered upon introduction of panobinostat. In addition, other parts of the innate immune system, including plasmacytoid dendritic cells and interferon-stimulated gene activity, also appeared to be linked to the decline in HIV DNA levels during panobinostat treatment.

According to Lichterfeld and colleagues, their results suggest that “innate immune activity may play an important role in reducing the latent reservoir” and is a promising target for future combined immune/drug approaches to curing HIV.

Dr. Laurence is amfAR’s senior scientific consultant.

amfAR Institute for HIV Cure Research: The Work Ahead

The Work Ahead

Paul Volberding, M.D., Ph.D.

Announced on World AIDS Day 2015 and launched with a $20 million grant to the University of California, San Francisco, the amfAR Institute for HIV Cure Research is up and running. A truly collaborative enterprise, the Institute’s work will be overseen by an executive committee comprised of Institute Director Paul Volberding, M.D., Ph.D., the principal investigators (see below), and amfAR’s Director of Research Rowena Johnston, Ph.D. The work will be divided into four modules—C, U, R, E.  

MODULE C: Chart

KEY QUESTION—Viral reservoirs: in which cells, in which tissues, in which people?

Principal Investigator: Mike McCune, M.D., Ph.D.

Mike McCune, M.D., Ph.D.

In this module, Dr. McCune and his colleagues will look at which tissues in the body harbor reservoirs of persistent HIV. They’ll be looking in particular at tissues in various regions of the gut and the female reproductive tract and comparing them with blood.  By carefully examining the tissues’ genetic information, both DNA and RNA, the researchers will get a sense of whether or not the virus is present and in which relative amounts in each area.

They will also look at which types of immune system cells in those tissues harbor the virus. In addition to what scientists believe to be the main reservoir, central memory CD4 T cells, what about macrophages or other types of T cells?

A critical question they will address is whether the HIV in these cells is capable of replicating. Since HIV mutates over and over again, in many instances errors occur in the virus’ DNA that render it incapable of forming an infectious virus. The researchers will use cutting-edge digital PCR technology to look at individual cells for defects in the viral genome. 

They will also examine the effects of age, sex, and the timing of ART initiation on the size, location and composition of the reservoir.

Finally, they aim to determine the effects of different experimental cure interventions in each cell subset and tissue of interest, and compare them across the various populations of HIV-positive people.  

MODULE U: Understand

KEY QUESTION—How to reverse latency and kill infected cells?

Principal Investigator: Warner Greene, M.D., Ph.D.

Warner Greene, M.D., Ph.D.

Researchers at the Institute will pursue variations of the ‘shock and kill’ strategy, which aims to awaken, or shock, HIV out of its latent state so that the cells harboring it can be targeted for killing by elements of the immune system. Dr. Greene and his team will test a number of ‘shocking’ agents that could potentially harness the body’s innate immune system in order to awaken and possibly even kill persistently infected cells.

The researchers will focus their efforts on so-called toll-like receptors (TLRs), a class of proteins that play a key role in the innate immune system.  They will test several drugs that can act on the receptors, TLR agonists, alone and in combination, in blood and tissue for their ability to reactivate virus.  They will then explore the mechanisms of action of those agents that are able to reactivate virus: do they exert their effects directly or indirectly? If indirectly, via which types of immune cells?  Can simpler and more specific means of delivering the same effects be devised?

INNATE IMMUNITY
The innate immune response is one of two main arms of the immune system. It delivers an immediate and potent, if unspecific, counterattack against infectious agents. By contrast, the adaptive immune response, the second arm, provides long-lasting protection by creating memory of specific invading pathogens that can be quickly recalled during subsequent encounters.

The team will then look at other classes of latency reversing agents (LRAs), such as HDAC inhibitors, BET inhibitors, and so-called noise enhancers, to see if they could be used to boost the effectiveness of TLR agonists.  Antibodies and other agents will be tested for their ability to kill infected cells that have been reawakened.
  

MODULE R: Record

KEY QUESTION—How much virus is in the reservoirs?

Principal Investigator: Satish Pillai, Ph.D.

Satish Pillai, Ph.D.

In this module, Dr. Pillai and colleagues seek to answer the question: How can we determine if our cure-designed therapies are having a meaningful impact on the persistent HIV reservoir? The case of the Mississippi baby demonstrates how critical a question this is. In 2013, this child, born with HIV, was believed to have been cured after being off antiretroviral therapy for more than two years. But the child eventually experienced a resurgence of HIV, proving that the available tools were simply not sensitive enough to detect virus that was present all along.

Dr. Pillai and colleagues will take several approaches to assessing the size of the reservoir using a range of cutting-edge technologies.  One of the challenges the researchers face is that the vast majority of HIV, having mutated and made imperfect copies of itself, is incapable of replicating. So they will work on methods of accurately differentiating between replication-competent virus and virus that is disabled and poses no threat. For example, they will sequence the virus and measure its ability to produce RNA or proteins. Detection of either one will suggest that a given virus is replication competent. 

They will examine HIV antibodies in the blood. Since these antibodies form when HIV is present and active in the body, they may provide an indication of whether and how much virus is present in tissues as well as in the blood.

And the researchers will use medical imaging techniques including PET and CT scans to directly visualize the presence and distribution of persistently infected cells. These technologies have the advantage of being non-invasive and give researchers the ability to scan the whole body and take a snapshot of the relative burden of virus in tissues throughout the body.
  

MODULE E: Eradicate

KEY QUESTION—How to safely eliminate the virus from the reservoir?

Principal Investigator: Steve Deeks, M.D.

This module will draw on knowledge gained in all of the other modules and will bring to bear the advanced techniques and technologies deployed and refined by all the collaborating research teams. Drawing all of these strands together, Dr. Deeks and his team will test the effectiveness of a range of interventions in human clinical trials. 

Steve Deeks, M.D. 

For example, the researchers will examine the effectiveness of TLR agonists, both alone and in combination, on the persistent reservoir and will also conduct a small clinical trial of a vaccine called GEO-D03, which also has a TLR component, in 30 individuals with HIV.  Using highly sensitive tests, including the assays employed by Dr. Pillai and his group, the trial participants will be tested periodically for evidence of reactivated cells and of decreases in the size of the reservoir. Information derived from Module C (see above) will guide their search for persistent virus in tissues and cells.

They will conduct another clinical trial of TLR agonists in collaboration with researchers at the Infectious Disease Research Institute (IDRI). This will involve reformulating these agents for nanoscale delivery by injection in six monthly doses. Information gained from Module U will help them understand the mechanisms by which the agents work. Understanding these mechanisms could help researchers fine-tune their interventions to make them even more effective.

They will also perform additional analyses of patients participating in several clinical trials of latency reversing agents and/or immune interventions that are currently underway.  

The amfAR Institute is a collaborative enterprise whose primary partners are UCSF, the Gladstone Institute of Virology and Immunology, and Blood Systems Research Institute. Additional collaborating institutions include the Infectious Disease Research Institute, Oregon Health and Science University, University of California, Berkeley, and Gilead Sciences. Expressing his optimism and his faith in the outstanding researchers under his command as director of the amfAR Institute, Dr. Volberding said, “We are dedicated to leading the way to a cure and believe our history, organization, resources and partners will allow us to remain at the forefront in this crucial final chapter of the HIV epidemic.” 

New amfAR Awards Accelerate Research Towards HIV Cure

NEW YORK, Oct. 22, 2015 --- amfAR, The Foundation for AIDS Research, on Thursday announced a new round of research grants totaling more than $1.4 million. The vast majority of the funding will support cure-focused research projects.

Renewal funding of $850,000 will go to a consortium of European researchers that aims to replicate the case of the “Berlin patient,” the first and only person known to have been cured of HIV. Diagnosed with leukemia, the patient was given a stem cell transplant with a twist: The cells he received were taken from a donor with a rare genetic mutation conferring resistance to HIV infection. He remains virus-free.

Working within the amfAR Research Consortium on HIV Eradication (ARCHE), a research program launched in 2010 to explore potential strategies for eliminating HIV, the scientists will study the outcomes of HIV patients who undergo different types of stem cell transplants. Led by Javier Martinez-Picado, Ph.D., of IrsiCaixa in Spain and Annemarie Wensing, M.D., Ph.D., of University Medical Center Utrecht in the Netherlands, the consortium has already identified a group of patients who have undergone transplants, and continues to monitor their progress in the hope of generating new knowledge that can inform more widely applicable interventions.

“We’re very excited to continue our support of the scientists in the European consortium,” said amfAR Chief Executive Officer Kevin Robert Frost. “They have made good progress since we began supporting their work last year, and they have real potential for significantly advancing the field of HIV cure research.” 

In addition, amfAR awarded a total of $600,000 to four promising young scientists who will each receive $150,000 over two years. These Mathilde Krim Fellowships in Basic Biomedical Research, named in honor of amfAR’s Founding Chairman Dr. Mathilde Krim, are awarded annually to nurture new talent within the HIV/AIDS research field.

Two of the Fellows will study aspects of the reservoirs of latent virus that are the main obstacle to eradicating HIV.

Luis Agosto, Ph.D., of Boston Medical Center, will explore a mechanism that involves the covert shuttling of HIV between cells, which could be an important factor by which the virus evades the immune response and thus may maintain the viral reservoir. Liang Shan, Ph.D., of Yale University in New Haven, CT, will use a humanized mouse model to test the efficacy of latency reversing drugs, studying their ability to reactivate HIV so that the immune system can kill those cells that harbor the virus.

Louise Scharf, Ph.D., at the California Institute of Technology in Pasadena, CA, will study the molecular structure of broadly neutralizing antibodies isolated from two HIV-infected patients to better understand how these powerful antibodies can help in the development of a vaccine against HIV.

And Amit Sharma, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle, WA, will explore how Rhesus macaques can be better utilized as an animal model in vaccine studies. Since the macaques are not susceptible to HIV and therefore cannot be used to study HIV specific antibodies, scientists have made viruses that are part SIV (the simian version of HIV) and part HIV, called SHIVs. However, not all SHIVs replicate efficiently, which limits their usefulness in the lab. Dr. Sharma is looking into what restricts the replication of some SHIVs but not others. His findings could help accelerate the field of vaccine research.

“The Krim Fellows are doing work that could produce major contributions to HIV/AIDS cure and vaccine research,” said amfAR Vice President and Director of Research Dr. Rowena Johnston. “Their projects are exciting and innovative, and we look forward to closely following their progress.”

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 the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested $415 million in its programs and has awarded grants to more than 3,300 research teams worldwide. Learn more about amfAR at www.amfar.org.

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Natural Killers Adapt

Dr. R. Keith Reeves

HIV vaccine strategists have a new and unexpected target in their sights: the natural killer (NK) cell. Writing in the September issue of Nature Immunology, researchers led by amfAR grantees Drs. R. Keith Reeves and Dan Barouch at Beth Israel Deaconess Medical Center in Boston reported, for the first time in primates, a new role for NK cells in the adaptive immune response.

The adaptive immune response, one of the two main arms of the immune system, provides long-lasting protection by creating memory of specific invading pathogens. This memory can be quickly recalled during subsequent encounters and is the basis on which vaccines are designed. The second arm of the immune system, innate immunity, delivers an immediate and potent, if unspecific, counterattack against infectious agents. NK cells have been traditionally thought to belong to the latter group, broadly killing target cells that are either virus-infected or cancerous.

The idea that NK cells belong strictly to the innate immune response began to change when studies in mice suggested that they can have a long-lasting memory of previously encountered pathogens. Reeves and Barouch, with colleagues from the New England Primate Research Center, Harvard Medical School, Ragon Institute of Massachusetts General Hospital, and the Heinrich-Pette-Institut in Germany, used macaques as models of HIV in humans to demonstrate that these special "adaptive NK cells" also exist in primates, and are major players in the immune response to HIV vaccines.

The researchers first showed that the NK cells were identifying their target cells based on whether they "matched" the virus in their memory bank. Then, to verify that the NK cells met the second criterion of adaptive immunity (i.e., a long-lasting response), they vaccinated animals with one of two different HIV-specific vaccines and waited five years before testing them. Again, they found that the NK cells, which first saw the vaccine five years ago, recognized and killed the matching target cells, leaving the mismatched cells largely untouched.

These results show that NK cells could be important in human vaccine strategies and we should move beyond targeting traditional cellular members of the adaptive immune response. "This gives us a brand new target," said Reeves. "We've been basing 30 years of vaccine research on essentially two types of adaptive immunity and now we have a brand new target…it is a really exciting proposition and it's a wide open area." Assessing NK cells' role in vaccine potency, as well as harnessing their various killing mechanisms, could be crucial in devising the most effective HIV vaccine.

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

Taking Control of HIV

Curing HIV will almost certainly require harnessing the ability of the immune system to kill infected cells, or at least control their ability to produce the virus. One important tool in the immune arsenal is CD8+ T cells, sometimes also called killer T cells. Scientists have long suspected they play an important role in bringing virus levels under control soon after infection. amfAR grantees Drs. Ann Chahroudi, Guido Silvestri, Mirko Paiardini, and others at Emory University, along with colleagues from Harvard Medical School, the University of Pennsylvania, and the Frederick National Laboratory for Cancer Research, set about understanding whether the ability of CD8+ T cells to control HIV comes via a direct effect (e.g., killing HIV-infected cells or reducing the amount of virus they can produce) or an indirect effect (e.g., preventing virus from spreading to new target cells). In the September issue of the Journal of Virology, they describe some surprising findings.

As in humans, in most monkeys infected with SIV, the simian version of HIV, viral replication eventually reaches a plateau and stabilizes, with some individuals reaching a higher viral load (VL) than others. To understand how CD8+ T cells contribute to setting the viral load plateau, or set point, all of the animals in this study—those with high or low VLs—were treated with an antibody to deplete CD8+ T cells. As expected, the removal of the CD8+ T cells resulted in an increase in the amount of virus throughout the body, and the fold change in the low-VL animals was greater than in the high-VL group, confirming that the presence of CD8+ T cells had been keeping VLs low.

amfAR grantee Dr. Ann Chahroudi talks about her research

But how were the CD8+ T cells exerting these effects? The researchers identified a genetic switch, called T-bet, in CD8+ T cells that predicted how much virus was present after those cells were depleted. T-bet is known to be important in controlling a range of activities of immune cells, including their survival, development, and function as mature cells. Even more intriguing, they found that not all subsets of infected cells were affected equally by CD8+ T cell depletion. In the absence of CD8+ T cells to control the virus, it might be expected that there would be an increase in viral DNA as VL increases and new cells become infected. That was the case in monkeys with high VLs. Surprisingly, however, monkeys with low VLs had a decrease in one subset of cells known to harbor latent virus, called central memory T cells (TCM). The drop in TCM was observed in both blood and in tissues. The authors hypothesized this may have been due either to the differentiation of those cells into effector memory T cells or to the killing of TCM as a consequence of viral production that was previously controlled by CD8+ T cells.

The latter possibility is especially interesting in the context of research aiming to cure HIV by using an approach known as "shock and kill," in which infected cells are manipulated to produce more virus and then killed as a result. The role that CD8+ T cells may play in promoting the death of virus-producing cells remains unclear and worthy of further study.

Dr. Johnston is amfAR's vice president and director of research.

To Reverse HIV Latency, Two Drugs Are Better Than One

Dr. Robert Siliciano

Use of combinations of antiretroviral drugs in “cocktails” to attack different parts of the HIV life cycle is the reason why most HIV-positive people maintaining undetectable viral loads can anticipate a normal lifespan. But the key obstacle to curing HIV remains the latent reservoir of virus, which is impervious to standard anti-HIV drugs. It has been a target of numerous research teams, many centered on a “kick and kill” approach by which dormant, HIV-infected cells are activated, rendering them susceptible to drug- and immune-based attack.

Such a strategy demands a robust shock to the latent state, but so far no single pharmacologic approach—using classes of drugs known as latency-reversing agents (LRAs)—has come close to the required potency. amfAR-funded scientist Dr. Robert Siliciano and colleagues at Johns Hopkins, Columbia, and Harvard Universities, writing in the May issue of The Journal of Clinical Investigation, have now put numbers on the amount of viral production an LRA needs to induce to be effective. Using the level of T cell activation required for maximum reactivation of dormant HIV in the test tube as the benchmark, the most potent drug tested thus far, bryostatin-1, could only get us 4% of the way.

A possible solution? Returning to lessons learned in designing antiretroviral therapy cocktails, Siliciano and associates explored two-drug combinations of mechanistically distinct LRAs. Using resting CD4+ T cells from HIV-positive individuals as targets, they found that certain LRA combinations acted synergistically to induce HIV growth. Equally important, this occurred without the release of proinflammatory immune hormones or cytokines, which can have deleterious side effects. They also developed a quantitative assay that uses the information gained from their test-tube studies to predict how effective the drug combinations might be in patients.

Dr. Laurence is amfAR’s senior scientific consultant.

Division or Multiplication: Exploring the Maintenance of the HIV Reservoir

Dr. Sarah Palmer

The remarkable stability of the reservoir of latent HIV in a patient on effective antiretroviral therapy (ART) is measured in many decades. But the mechanisms by which this is achieved are under debate. Two possibilities are: 1) the viral reservoir may maintain its size by infected cells continuing to produce virus that infects other cells while killing the original infected cell; 2) an infected cell may remain quiescent, or inactive, in terms of producing virus but may make copies of itself, with at least one daughter cell containing the virus.

In last month’s update we noted the work of amfAR fellow Dr. Remi Fromentin of the University of Montreal, who is exploring the very low levels of viral production that are characteristic of many models of the HIV latent state. Writing in the August issue of the Journal of Infectious Diseases, amfAR-funded scientists Dr. Sarah Palmer of the University of Sydney and Drs. Frederick Hecht, Hiroyu Hatano, and Steven Deeks at the University of California San Francisco, with colleagues from the Karolinska Institute in Stockholm, the Rega Institute for Medical Research in Belgium, and the Frederick National Laboratory for Cancer Research and the National Institutes of Health, investigate two much greater contributors to such reservoir stability: growth and differentiation of infected cells.

Dr. Palmer and associates undertook an intensive genetic study of integrated viruses from eight individuals on ART. They isolated the HIV proviruses not only from patients’ blood but also from intestinal and lymph node biopsies. They repeated these studies seven to nine months apart and found that the major home for latent virus—the memory T cell—was maintained mainly by cellular proliferation and longevity of the infected cells itself, rather than by ongoing viral replication.

These data support a critical conclusion: strategies for destroying the latent HIV reservoir might need to be more efficient than the growth of infected cells. And the level of difficulty in achieving this will depend upon exactly where that virus sits inside a particular cell—whether within or apart from a proliferating gene. Dr. Eunok Lee, one of the study’s co-authors, working in the laboratory of Dr. Palmer, won the Lange-Van Tongeren Prize for Young Investigators at the eighth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Vancouver earlier this year for this work.

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

Cure Matters: Conversations with Leading HIV Researchers

What cure-focused projects are the world’s foremost AIDS researchers working on? What are the most promising recent developments in the field of cure research? And how close are we to finding a cure? In a series of interviews at the International AIDS Society conference in Vancouver this summer, amfAR put these and other questions to several current grantees.

Dr. Benjamin Burwitz of Oregon Health and Science University, Portland, is trying to determine the mechanism of action that led to the first and only known HIV cure in "the Berlin patient" by attempting to recreate the case in nonhuman primates.

Dr. Paula Cannon of the University of Southern California, Los Angeles, is attempting to engineer HIV-proof immune cells, as well as investigating latent reservoirs in the brain.

Dr. Ann Chahroudi of Emory University School of Medicine and Yerkes National Primate Research Center, Georgia, is using nonhuman primate models to evaluate HIV reservoir persistence.

Dr. Timothy Henrich of the University of California, San Francisco, is investigating new drugs aimed at boosting the immune system’s ability to clear the body of HIV.

Dr. Brad Jones of George Washington University, Washington, D.C., is focusing on a specific drug that both reactivates latent HIV and enhances the immune system’s ability to kill infected cells.

Dr. Marta Massanella of the University of California, San Diego, is studying a recently discovered subset of CD4 T cells believed to contribute heavily to the latent HIV reservoir.

Dr. Satish Pillai of Blood Systems Research Institute and University of California, San Francisco, is studying natural factors that affect the size of the latent HIV reservoir.

American Health Journal Highlights amfAR’s Work to Find HIV Cure

Stabilize or Stimulate? A New Approach to Attacking the HIV Reservoir

A recurring message in our research updates relating to HIV cure strategies is the importance of eliminating the latent viral reservoir—infected memory CD4+ T cells harboring pockets of HIV in their DNA. While antiretroviral therapy (ART) can reduce HIV in the blood to undetectable levels, it fails to permanently purge the virus from this silent sanctuary. 

Addressing this drawback of standard anti-HIV drugs, a team of scientists, including amfAR fellow Dr. Remi Fromentin and ARCHE grantee Dr. Nicolas Chomont of the University of Montreal, former amfAR fellow Dr. Susana Valente of the Scripps Research Institute in Florida, and colleagues from the Vaccine and Gene Therapy Institute of Florida and the U.S. Military HIV Research Program in Maryland, tested a novel approach to attacking the HIV reservoir.

Dr. Remi Fromentin

Dr. Nicolas Chomont

The most widely studied strategy for wiping out the HIV reservoir, dubbed “kick and kill,” uses drugs to spur latently infected cells into producing virus so that they can be identified and destroyed by the immune system or antiretrovirals. Writing in the July issue of mBio, Fromentin and associates describe their study of a new drug called didehydro-cortistatin A (dCA) that does the opposite: it inhibits reservoir activity.

Dr. Nicolas ChomontAn analog of the natural product cortistatin A, which is derived from a marine sponge found in Southeast Asia, dCA targets the viral gene activator Tat. The Tat protein greatly increases HIV growth by enhancing its ability to replicate. Using several test tube models of HIV latency, the team found that by blocking Tat activity, dCA reduced the low-level viral production characteristic of the HIV latent state. Treatment with dCA also blocked virus reactivation, establishing “a nearly permanent state of latency.” Importantly, this inhibition persisted even after the drug was withdrawn. Follow-up testing in animal models is clearly required.

The authors conclude that their results highlight an alternative approach to the “kick and kill” strategy—stabilization rather than activation of latent pools of virus—and that dCA could be a valuable adjunct to current ART regimens. With reservoir activity (i.e., replication, reactivation, and replenishment) halted, the natural death of the infected cells could occur, resulting in the “continuous decay of the pool over time, possibly culminating in the long-awaited sterilizing cure.”

Dr. Laurence is amfAR’s senior scientific consultant.

New amfAR Grants Accelerate Research Efforts to Eradicate HIV

Three research teams awarded $2 million each over four years to conduct basic, animal and clinical studies

NEW YORK, July 21, 2015 --- amfAR, The Foundation for AIDS Research, announced that three research teams have been awarded $2 million each to pursue a range of strategies aimed at curing HIV. The new grants are part of amfAR’s $100M Countdown to a Cure initiative, launched last year with the aim of discovering the scientific basis for a cure by 2020. Each project is designed to tackle the major impediment to curing HIV, namely the persistence of the virus despite anti-HIV drugs. 

"At $2 million each, these new grants represent the continued expansion of amfAR’s investments in research to find a cure for AIDS, and they are among the largest grants we have ever awarded.  They are a reflection of our optimism around cure research and our collective determination to invest $100 million over the next five years in order to develop the scientific basis of a cure for this disease," said amfAR Chief Executive Officer Kevin Robert Frost. 

A team of researchers led by Dan Barouch, M.D., Ph.D., of Beth Israel Deaconess Medical Center in Boston, Massachusetts, will investigate the ability of combinations of antibodies to specifically kill latently infected cells in the lab, in monkeys, and then in people. The researchers will test two promising antibodies alone and together, in combination with a newly described drug that can “shock” the virus out of latently infected cells and possibly enhance the ability of the antibodies to locate the infected cells.

Timothy Henrich, M.D., of the University of California, San Francisco, and his colleagues will pursue a novel intervention aimed at restoring normal immune function in people with HIV. The team will test whether the transplant drug, sirolimus, can increase the activity of beneficial components of the immune system while suppressing detrimental activity of other components. The team will thoroughly assess the drug’s activities before moving on to test the drug on persistent HIV reservoirs in people. 

Using an approach that has already proved successful in cancer therapy, Sharon Lewin, FRACP, Ph.D., of the University of Melbourne, Australia, will explore whether drugs that block so-called immune checkpoints can also be effective against HIV. Researchers theorize that the immune system cannot eliminate infected cells because of immune checkpoints, a set of mechanisms that limit the duration of an immune response so that the immune system does not become exhausted.  Dr. Lewin and her team will test two drugs, alone and together, for their ability to reverse immune exhaustion and restore the ability of the immune system to eliminate infected cells. 

“These four-year grants are a departure for amfAR and an important pillar of our cure research strategy,” said Rowena Johnston, Ph.D., amfAR vice president and director of research.  “They allow teams of leading researchers to take their ideas across the research continuum—from lab studies to human trials. We’ll be following their progress with great interest.”