In a novel approach to conquering HIV, amfAR, The Foundation for AIDS Research, is pairing HIV researchers with bioengineers to address the main barrier to a cure for HIV: the persistent reservoirs of virus not cleared by antiretroviral therapy. A new round of Investment grants, totaling $1.2 million, will support six new research projects aimed at bringing to bear highly advanced technologies that until recently might have belonged in the pages of a science fiction novel.
Scientists at Case Western Reserve University School of Medicine have received $2.5 million from the pharmaceutical company Gilead Sciences to test two never-before-combined HIV treatments on patients.
Gene therapy — which involves modifying genetic material, such as DNA and RNA — holds exciting potential as a cure for numerous diseases and conditions, including HIV.
HIV persists in immune cells and in certain tissue compartments such as the brain and gut despite our best antiretroviral therapies (ART). Writing in the March issue of Current Opinion in HIV and AIDS, amfAR-funded scientists Marta Massanella, Rémi Fromentin, and Nicolas Chomont, all from the University of Montreal, focus on persistent inflammation in ART-treated individuals as a major driver of such viral persistence.
A network of leading HIV/AIDS researchers are continuing to pave the road toward a cure for HIV with a boost of funding on Wednesday from amfAR, the Foundation for AIDS Research. The research grants, totaling more than $913,000, will enable five teams of scientists working at leading research institutions in the United States and around the globe to collaborate on studies aimed at curing HIV.
An HIV-infected T cell (Source: NIAID)
Interest in the role of antibodies—traditionally thought of as a vital component of any vaccine designed to prevent HIV infection—has been growing in the context of HIV cure research. This was reflected in a meeting— Development of Monoclonal Antibodies for HIV Treatment and Cure—convened by the National Institutes of Health and the Gates Foundation, June 3–4, in Rockville, MD.
Antibodies are generally thought of for their ability to neutralize virus that has not yet infected cells, whereas the main stumbling block in curing HIV is cells that are already infected. But antibodies have additional functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), that can directly target infected cells. ADCC occurs when a cell of the immune system—an effector cell such as a natural killer (NK) cell—binds to an antibody that in turn binds to the surface of an infected cell. The NK cell can then kill the infected cell.
Writing in the May issue of the Proceedings of the National Academy of Sciences, amfAR fellow Dr. Navid Madani of Harvard Medical School and a large team of researchers described a method of boosting the ability of antibodies to kill HIV-infected cells via ADCC. The ADCC effect hinges on the presence of the Env protein on the surface of infected cells. Env originates on the surface of the virus and binds to CD4 proteins on susceptible cells. After infection, some Env remains on the cell surface.
HIV protects itself from antibody attack by using two of its own proteins, Nef and Vpu, to decrease exposure of Env on the cell surface. To override this mechanism, Madani and colleagues used various forms of infecting virus, as well as variations of the CD4 protein, to enhance the ADCC-mediated killing of infected cells generated in a petri dish, as well as in cells taken from HIV-positive individuals. The authors envision that the combination required for this approach might be delivered by vaccine (for the antibodies) plus an oral formulation of modified CD4 proteins.
Dr. Madani collaborated with researchers from the University of Montreal; University of Pennsylvania; Institut de biologie et de technologie de Saclay, France; University of Maryland; Johns Hopkins University; the Scripps Research Institute; and Duke University.
amfAR recently funded another project that will combine the antibody 3BNC117—optimized for ADCC—with the cancer drug romidepsin, the most promising agent to date in terms of its ability to shock the virus out of latency. For more details, click here.
Dr. Johnston is amfAR’s vice president and director of research.
Dr. Mirko Paiardini
Most research approaching an HIV cure has centered on T cells in the blood. This is understandable, given ready access to such samples. But it is now apparent that, both in HIV-infected humans and in SIV-infected monkey models, one of the very first immunologic events early after infection is severe depletion in the intestines of certain specialized T cells, Th17 and Th22. These cells are recognized by their production of two immune hormones, the interleukins IL-17 and IL-22, respectively. Writing in the February issue of the journal PLoS Pathogens, amfAR-funded scientist Dr. Mirko Paiardini of Emory University, together with colleagues there and at the University of Montreal, report on the function of these cells and the ability of antiretroviral therapy to maintain the cells’ function after infection.
The researchers found that these cell types in healthy monkeys and humans produced at least five critical cytokines necessary to maintain integrity of the intestinal lining. The level of their depletion after an SIV infection in their experimental monkey model directly correlated with levels of immune activation, established early after an infection. Following treatment with ART, improvement in terms of Th17 T-cell number and function inversely correlated with levels of virus in the animal’s blood. In other words, the higher the level of virus, the less recovery there was in the function of IL-17-producing cells. On the flipside, more of those intact cells predicted less of the virus.
Of great significance for studies of potential HIV cures, it was found that after stopping ART in the infected monkeys—as would be done as part of an analytic treatment interruption, or ATI (to help establish that an individual with no detectable virus after an experimental cure trial was truly virus-free)—both Th17 and Th22 T cells were rapidly and severely damaged.
The authors concluded that it was important to preserve intestinal T17 and T22 T-cell function during HIV infection. They emphasized the need for “therapeutic strategies aimed at improving these cells’ function in future HIV cure research.”
An award-winning image of CTLs attacking a tumor cell (Photo: Sudha Kumari)
Dr. Jones is the recipient the first amfAR grant to be funded by generationCURE, a group of young professionals dedicated to advancing amfAR’s efforts to find a cure for HIV. 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. Eradicating the cells that harbor that virus is the goal of research aimed at a sterilizing cure (in which all virus is completely eliminated from the body). One approach being taken by researchers to accomplish such a cure is to recruit the help of a subset of immune cells charged with clearing the reservoir.
Natural killer (NK) cells and cytotoxic T cells (CTLs) mediate the killing of virally infected cells and, in the case of CTLs, can be specific for HIV. Much research has been devoted to retraining CTLs to be better killers of HIV-infected cells. Writing in the February issue of The Journal of Clinical Investigation, Drs. Brad Jones and Bruce Walker review the properties of CTLs that could be exploited as part of a cure for HIV.
Dr. Jones is Assistant Professor in the Department of Microbiology, Immunology and Tropical Medicine at The George Washington University. He gained expertise in CTLs during his postdoctoral work in the lab of Bruce Walker, who was one of the first to describe CTLs in HIV-infected persons. Dr. Jones has published numerous studies on CTLs and continues to pursue his research with a grant from amfAR’s generationCURE. Here, he shares his views on the latest approaches being used by scientist to harness CTLs in the search for a cure for HIV.
You recently published a review article with Dr. Bruce Walker on the role of CTLs in HIV cure studies. What makes this topic especially timely?
Dr. Jones is the recipient of the first amfAR grant to be funded by generationCURE, a group of young professionals dedicated to advancing amfAR’s efforts to find a cure for HIV.
CTLs, also known as CD8+ T cells, are cells of the immune system that specialize in recognizing and killing virus-infected cells. I always find it inspiring to see these guys in action—moving quickly through tissues and hunting for virus-infected cells. When a CTL encounters an infected cell it rapidly discharges toxic proteins, killing the target cell, essentially eliminating a virus factory. The sensitivity and specificity of this killing is really impressive.
Even more impressive is the impact CTLs can have in a clinical setting. Louis Picker, Jonah Sacha, and colleagues in Oregon, for example, have developed a means of eliciting a CTL response that is capable of completely eradicating SIV (the monkey version of HIV) from animals. The CTLs elicited in this study have a very unusual way of recognizing infected cells, but serve to illustrate the power of these types of cells if they can be properly directed.
“I always find it inspiring to see these guys in action—moving quickly through tissues and hunting for virus-infected cells.”
The challenges involved in either completely eradicating HIV infection (sterilizing cure) or enabling the immune system to control infection long-term (functional cure) are both considerable. In my opinion, our best chance at achieving these goals centers on finding ways to aim and enhance the natural antiviral weapons in our immune system, such as CTLs, against persistent virus.
Why do CTLs fail to clear HIV infection?
There are several factors at play here. The classical explanation would be that CTLs cannot recognize the viral reservoir because it hides in a latent state. This is certainly part of the answer, but I would speculate that there is some ongoing interaction between CTLs and the viral reservoir, even in individuals with undetectable viral loads.
Another part of the explanation is that HIV has an uncanny ability to mutate in order to ‘escape’ detection by CTLs. We also know that CTLs become ‘exhausted’ when faced with persistent infections such as HIV and less effective at eliminating infected cells. However, there is still a lot that we don’t know. Several labs, including my own, are interested in determining what makes a CTL particularly effective against the viral reservoir so that we can hopefully elicit these responses therapeutically.
What are some of the approaches scientists are using to make CTLs more effective?
I would highlight two studies that I am involved in. In one project funded by amfAR’s generationCURE, we are studying a drug that has the potential to act as both an immunomodulation agent and a latency-reversing agent – thus simultaneously exposing infected cells to CTLs and enhancing the ability of CTLs to kill these targets. In a second project we are exploring immunomodulation using an antibody that enhances the activity of IL-21, a molecule that improves the killing ability of CTLs.
Definitions:
Immunomodulation: The use of drugs or biologics (antibodies, cytokines, etc.) to alter the immune response.
Latency reversal: Latency-reversing agents wake up dormant HIV and facilitate elimination of infected cells.
Dr. Michel Nussenzweig is working with colleagues to test broadly neutralizing antibodies in a combination cure approach in an amfAR-supported clinical trial.
Dr. Michel Nussenzweig is working with colleagues to test broadly neutralizing antibodies in a combination cure approach in an amfAR-supported clinical trial.Are there any CTL-focused trials currently in the clinic?
Yes, there are quite a few trials of therapeutic HIV vaccines aimed at enhancing CTL responses, including some that combine vaccination with latency-reversing agents to try to ‘shock and kill’ the reservoir. Cath Bollard, in collaboration with David Margolis, is also in the process of testing CTL therapy – whereby HIV-targeting CTLs are isolated from participants, expanded and then re-infused, with the hope that these will drive reductions in the reservoir. I’m anxiously awaiting the results from these studies. If we can see a signal that the reservoir is significantly reduced in some individuals, then we will have something that we can grab onto and further improve upon – this is really the breakthrough that we are all working towards.
What strides have been made in HIV cure research that make you hopeful that we will find a cure, sterilizing or functional, in the near future?
In regard to a sterilizing cure, I would again point to the work of Louis Picker, Scott Hansen, Jonah Sacha and others at Oregon Health Sciences University with their demonstration that an unusual type of T cell response is able to eradicate SIV infection from monkeys. There are some key limitations of the current form of this intervention – first, the vaccine has thus far been given before an animal is infected and, second, it is only effective in approximately 50% of animals. However, to my knowledge, this is the first and only example of immune-mediated elimination of infection with a lentivirus.
“I commend amfAR for being highly involved in pushing this research forward.”
Stepping away from CTLs for a moment, I am also encouraged by the work being performed with broadly neutralizing antibodies as reported by Michel Nussenzweig, James Whitney, Dan Barouch, and others. We have an incredible arsenal of very effective antibodies available and evidence is mounting that these can be used to target the viral reservoir. I commend amfAR for being highly involved in pushing this research forward.
Gilead has presented exciting data showing that a small-molecule TLR-7 agonist is able both to reverse HIV latency and to enhance the functions of both CTLs and NK cells, representing a potentially powerful combination.
In relation to a functional cure, the phenomenon of post-treatment control of HIV for individuals who started treatment early in infection, best represented by the VISCONTI cohort in France, provides an important precedent that long-term immune control is possible. If the mechanisms underlying this control can be determined, then we will have a path forward to attempt to induce the appropriate responses in a broader array of individuals.
There is really a tremendous amount to be excited about in this rapidly moving field and we are extremely fortunate to be working with a community that is supportive of our efforts, both in terms of financial support and by volunteering to participate in clinical studies. As long as we continue to pull together, we will achieve the goal of curing HIV – either through one of the approaches highlighted above or, perhaps, through something entirely unexpected.
A plasmacytoid dendritic cell (blue) interacting with a T-cell (pink).
Our immune systems offer a very rapid, non-specific first line of defense against invading viruses. These innate pathways lack the specificity and memory characteristic of our more mature immune defenses, which can take weeks to evolve, but they are essential in the control of many infectious diseases. Writing in the June issue of The Journal of Infectious Diseases, amfAR-funded scientist Dr. R. Keith Reeves and colleagues from Harvard Medical School and the New England Primate Research Center dissect the role of one of these early defenses in the control of HIV.
Using a monkey model for AIDS—SIV infection in the macaque—Reeves and associates examined CD4+ plasmacytoid dendritic cells (pDCs), a potent source of interferon-alpha. By bringing interferon to sites of viral invasion and growth, pDCs can inactivate many viruses before they have a chance to replicate and spread. They can also amplify the killing effects of another form of innate immunity against viruses, natural killer cells. The importance of pDCs is emphasized by the fact that they are present at high levels in elite controllers of HIV infection, but are depleted in most humans, and monkeys, soon after infection occurs. They rise again after the introduction of antiretroviral therapy.
But how much of a trade-off does this innate, interferon-based defense present in the context of HIV? It is a key concern because too much interferon leads to inflammation in the gut and other tissues. As regular readers of these updates will recognize, inflammation contributes to HIV growth, and to premature aging of the heart, kidney, and bones in HIV-positive individuals.
Reeves and colleagues discovered that the production of interferon by pDCs occurred too late to control acute SIV infection. Additionally, pDCs failed to migrate to and accumulate in the gut—a major source of early SIV and HIV growth—until after virus levels were well established in the blood. And they may also be pathologic, contributing to ongoing immune activation. Whether this system should be modulated as part of strategies to enhance the control, and eventual cure, of HIV requires further investigation.
Dr. Laurence is amfAR’s senior scientific consultant.
A variety of different approaches to HIV eradication have been discussed in these updates. But this update is a bit different, describing a critical issue: How might we better assess the likelihood of HIV resurgence after stopping ART and, if possible, the probable time frame for such a recurrence, in a given patient?
Dr. Timothy Henrich
Writing in the January issue of The Lancet HIV, amfAR-funded scientists Timothy Henrich of the University of California, San Francisco (UCSF), and Sharon Lewin of the University of Melbourne, with colleagues from Johns Hopkins University and UCSF, note that a stem cell transplant approach that replicates the experience of the “Berlin patient” remains “the only approach that has led to a meaningful decrease in latently infected cells in individuals on ART."
The Berlin patient is a formerly HIV-positive man with leukemia, who in 2008 became the first and only person known to have been cured of HIV after he received a stem cell transplant from a donor with a rare genetic mutation (the CCR5 mutation) that confers resistance to HIV infection. The authors state that such a procedure remains “the only approach that has led to a meaningful decrease in latently infected cells in individuals on ART.” The most definitive way to document another such cure, as a result of stem cell transplantation or any other intervention, requires that the person be taken off anti-HIV drugs.
Dr. Sharon Lewin
But this so-called analytical treatment interruption has risks, which raise several ethical questions. Particularly in the realm of stem cell transplantation, aggressive viral rebound has been seen, with associated morbidity, possible mortality, and a chance of the emergence of a drug-resistant virus. Risks to sexual partners in case of such rebound must also be recognized. The need for very close, very frequent monitoring with available technologies to assess viral load and latent virus reservoirs is cumbersome, costly, and may involve years of surveillance.
But, as Henrich and associates note, “An understanding of the mechanisms by which [these transplants] can result in sustained ART-free remission or the reasons why it fails to do so could reveal key information to advance HIV cure research.”
With these concerns in mind, amfAR is hosting a think tank in Memphis in early March to try to identify methods by which HIV relapse can be predicted following a treatment interruption related to a cure trial. We’ll keep you informed.
Dr. Angela Wahl
Most infants breastfed by an HIV-positive woman do not become infected. It has long been known that components of human breast milk from HIV-negative mothers can inhibit the growth of HIV in the test tube, indicating that HIV-specific antibodies in milk are not responsible for this activity. But until Dr. Angela Wahl, an amfAR Krim Fellow, began her studies, no one had explored such a phenomenon in HIV-positive women.
Writing in the November 2015 issue of the Journal of Virology, Dr. Wahl, working at the University of North Carolina in Chapel Hill, along with colleagues from Duke, Harvard, Columbia, UC-San Diego, and the University of Southern California, explored the activity of milk derived from HIV-positive women from Zambia who had breastfed their infants and either transmitted the virus or not. Rather than limiting experiments to test-tube studies and oral transmission, Dr. Wahl used “humanized mice” carrying components of a human immune system, and explored vaginal and intravenous HIV transmission as well.
All humanized mice exposed orally, vaginally or intravenously to small doses of HIV became infected. In contrast, only a quarter of the animals became infected when the virus was introduced orally along with human breast milk. It was 25% regardless of whether the milk came from known virus transmitters, or those Zambian women who breastfed and did not transmit. Significant protection was also obtained using virus administered with breast milk by the vaginal and intravenous routes.
The nature of the active components in human breast milk that are responsible for this protective effect remains unclear. The activity was not found in milk from cow, camel, goat, or monkey. It was not destroyed by pasteurization or by manipulations designed to remove or destroy protein, sugars, or fat. The authors concluded that the activity most likely involved an interaction among those three components.
Given the nutritional and immunologic benefits of breast milk, and the dangers of preparing infant formula when clean water cannot be guaranteed, these data bolster current recommendations that HIV-positive women in resource-poor nations exclusively breastfeed in combination with antiretroviral therapy. The promise is that identification of the components responsible for the anti-HIV activity might form the basis for the development of natural microbicides—substances that could be applied topically to prevent acquisition of HIV infection—or other anti-HIV medications.
Dr. Laurence is amfAR’s senior scientific consultant.
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.”
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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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.
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.
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.
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.
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.
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).
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.
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
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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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.
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 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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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.
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.
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.
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.
