Sex and the HIV Reservoir

New research points to the powerful effect of estrogen

A newly published study reveals that the female hormone estrogen has a significant effect on the persistent HIV reservoir. It suggests that women may respond differently than men to some curative interventions that are currently under investigation or, perhaps, that an effective cure for women could differ from a cure for men.

 Dr. Jonathan Karn (Photo: Marcus Rose/IAS)

Dr. Jonathan Karn (Photo: Marcus Rose/IAS)

The reservoir of HIV that is impervious to antiretroviral therapy remains the principal barrier to a cure. Following a cohort of 26 men and 26 women, the researchers, led by Dr. Jonathan Karn of Case Western Reserve University, found that women have a smaller “inducible” reservoir than men. In other words, while the total size of the reservoir appears to be the same for both sexes, women have a smaller amount of reservoir virus that can be coaxed out of hiding by so-called latency-reversing agents (LRAs).

The finding has several important implications. First, one of the main cure strategies being pursued by researchers is “shock and kill” (or “kick and kill”). The intent is to shock HIV out of the reservoir so that it can be killed by the immune system or some other killing agent. Given their smaller inducible reservoir, would such a strategy be less effective in women?

Second, since reactivation of the reservoir is inhibited by estrogen, the researchers suggest that “studies of the impact of hormonal contraception on reservoir establishment and its long-term maintenance should be undertaken.”

And, given the small size and exploratory nature of cure-focused clinical studies to date, the inclusion of women in small clinical trials may lead to skewed results if hormone exposure is not considered.

The study concludes that further investigations into sex differences in latency reversal and HIV persistence “are mandatory to extend the benefits of the HIV cure effort to all men and women impacted by the global epidemic.”

Published in the Proceedings of the National Academy of Sciences, these findings are the most recent outgrowth of a multi-year amfAR investigation into sex differences in HIV. “We’ve long known that women and men differ in immune system function and response to antiretroviral therapy, but few researchers have followed up on these leads in cure research,” said amfAR Vice President and Director of Research Dr. Rowena Johnston, a co-author of the study. “It is imperative that we develop a cure that works for everyone.”

In 2012 Dr. Johnston was invited to give a talk on sex differences in HIV cure research at a conference. She soon realized, however, that there were very little available data on the topic. So she teamed up with Dr. Mary Heitzeg of the University of Michigan to undertake a systematic review of more than 150 published HIV cure research studies.

“It is imperative that we develop a cure that works for everyone.” —Dr. Rowena Johnston

The study, published in 2015, found that while there was a strong possibility that the efficacy of a potential cure could vary by demographic variables, only 8% of the studies reported conducting efficacy analyses by sex. They concluded that, “More data are needed to determine associations between demographic characteristics and safety/efficacy of curative interventions.”

Responding to this need, in 2016 amfAR awarded a grant to two teams of researchers led by Dr. Karn and Dr. Eileen Scully of Massachusetts General Hospital to explore how sex-based differences might affect the HIV reservoir and, by extension, a potential cure. The researchers were tasked with comparing the key differences in latent virus in men and women, and exploring the immune profile, activation levels and distribution of latent viral reservoirs in men versus women.

Their first set of findings, detailed in the PNAS paper, lay the groundwork for a preliminary trial to evaluate the effectiveness of the drug tamoxifen combined with the latency-reversing agent vorinostat in reactivating latent HIV in women.  Supported by the National Institutes of Health’s AIDS Clinical Trials Group, the study is expected to conclude in September 2019.  

The CD8 T Cell in HIV: New Insights from Tissue vs. Blood

For obvious reasons, physicians rely on peripheral blood samples to describe the state of the immune system in an HIV-infected individual, and follow the impact of antiretroviral therapies on activity of the virus and immune function. But new data from a large international collaboration that included amfAR-funded scientist Dr. Steven Deeks, suggest that most prior studies, all involving blood, failed to consider a major component of the body’s attack against HIV: the resident memory CD8 T cell, or CD8 TRM.

 Dr. Steven Deeks

Dr. Steven Deeks

Writing in the June issue of Science Immunology, Dr. Deeks, from the University of California, San Francisco, and colleagues* emphasize that the CD8+ killer T cell is required for effective immune control of HIV. However, this type of immune cell exists in three forms. Only two, the central memory and effector memory T cells, circulate in blood. The third form, TRM, resides in lymphoid and non-lymphoid tissues. Yet these TRM cells establish a front line of defense to eliminate invading viruses and bacteria, and do so largely without involvement of circulating CD8 T cells.

Deeks and associates demonstrate that TRM cells dominate the CD8+ killer T cell response against HIV in lymph nodes and other lymph tissue throughout the body. They obtained tissue samples from HIV-infected individuals in the acute and early stages of infection. The highest frequency of these cells was found in “elite controllers,” individuals who maintain very low levels of HIV in the absence of ART.

This discovery has several implications. Importantly, it is known that the potency of certain experimental vaccines against SIV, the simian form of HIV, in monkeys can be predicted from the magnitude of virus-specific CD8 T cells in the lymph tissue of these animals. Expanding knowledge of the activity of the CD8 TRM cells in these tissues should, as the authors conclude, inform “new approaches to the development of vaccines or immunotherapeutic strategies designed to eliminate the viral reservoir in established HIV infection.” In other words, help us reach a cure.

*From the University of Pennsylvania, the Karolinska Institute in Stockholm, the Instituto Nacional de Enfermedades Respiratorias in Mexico City, the National Institutes of Health, the University of Minnesota, Emory University, Case Western Reserve, and Cardiff University in Wales.

Dr. Laurence is amfAR’s senior scientific consultant.

A New Source of Latent HIV?

amfAR-funded researchers continue to study cells other than CD4+ T cells that may harbor latent HIV. Such cells may pose additional obstacles to an HIV cure. Last month’s update featured amfAR grantee Dr. Paula Cannon and her work on specialized cells in the brain. In a study published online in May in The Journal of Clinical Investigation, amfAR grantee Dr. Luis Agosto and colleagues from Boston University look at possible HIV reservoir cells in the vagina.

 Dr. Luis Agosto

Dr. Luis Agosto

Agosto and associates obtained vaginal biopsies from five HIV-negative women and two women with HIV who were receiving antiretroviral therapy. First, they documented that a special type of immune cell, known as a vaginal epithelial dendritic cell (VEDC), could be infected with HIV in the test tube. VEDCs are recognized by their shape, a characteristic internal structure on electron microscopy, and specific cell surface proteins.

But their research went further, showing that these cells were much more susceptible to infection by those strains of HIV that utilize a certain cell surface protein—known as CCR5—to enter a cell, rather than an alternative protein receptor, CXCR4. Based on their findings, the authors suggest that VEDCs may be strict “gatekeepers” for infection, selecting which strains of HIV will establish an infection in a woman.

The researchers also examined the possibility that VEDCs could establish a reservoir of latent virus. They found evidence that this may indeed be a possibility by identifying proviral HIV DNA in VEDCs obtained from the two HIV-positive women. By sequencing the DNA, they established that the VEDCs harbored “ancestral” fragments of HIV (the founder virus that established infection) in the women.

The number of such proviruses per VEDC was four- to eight-fold lower than those found in the women’s blood cells, but the amount was still highly significant. 

More work needs to be done to definitively conclude that vaginal cells are part of the latent HIV reservoir. It is possible that the VEDCs simply scavenged pieces of latent virus from T cells and could not produce infectious viruses when stimulated—the test of a true latent reservoir.

Dr. Laurence is amfAR’s senior scientific consultant.

Neutrophils: A Deadly, if Delicate, Killer

 Dr. Amy Chung

Dr. Amy Chung

Researchers have long focused on natural killer (NK) cells as the principal cells of the immune system that receive a signal via antibodies to kill HIV-infected cells. In the May issue of the Journal of Immunological Methods, amfAR Krim Fellow Dr. Amy Chung and colleagues shed new light on this topic by highlighting the role of neutrophils, a more numerous and much more difficult cell to study, and their less well studied role in killing infected cells via antibodies.

Unlike NK cells, which can persist for years, neutrophils live less than a week inside the body. Outside of the body, they die easily within a few hours and react so quickly to their new environment that, in a petri dish, they no longer resemble the cells the researchers set out to study. While it is known that neutrophils use antibodies to direct their killing ability towards HIV-infected cells, the mechanisms through which they do so remain a mystery.

A neutrophil

To spur this research, Dr. Chung developed a tool to study how antibodies in a patient’s blood might team up with neutrophils. To get around studying the fragile neutrophils in healthy blood, Dr. Chung developed the tool using cells from a cancer patient who donated her cells to science. It was Robert Gallo, one of three scientists credited with discovering that HIV causes AIDS, who archived the cells in 1977. In a petri dish, these cancerous cells can live indefinitely and maintain many of the same characteristics as fresh neutrophils.

Using this tool, Dr. Chung found, surprisingly, that neutrophils were six times better able than NK cells to kill HIV-infected cells when antibodies were present. The authors note that “neutrophil-mediated effector responses should be investigated in future HIV vaccine trials.”

Given what the field is learning about the diverse activities of antibodies (see here and here, for example), there is real potential for neutrophil function to also play an important role in an HIV cure.

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

HIV in the Brain

 Dr. Paula Cannon

Dr. Paula Cannon

Most studies of the latent HIV reservoir, the primary impediment to a cure, focus on T cells. But amfAR grantee Dr. Paula Cannon, working at the University of Southern California with colleagues there and at Case Western Reserve University, has taken a different approach. She notes that the brain also contains distinct populations of three specialized cells infected with HIV: microglia, astrocytes, and macrophages. She sought to develop a mouse model to study these cells and their role in HIV latency.

Writing in the April issue of the Journal of Neurovirology, Cannon and associates emphasize the difficulty of studying brain cells from HIV-infected humans. In addition, the differences between simian immune deficiency virus and HIV make the monkey a less-than-ideal model for studying HIV in the brain. Instead, she used “humanized mice”—immune deficient animals transplanted with human blood-forming cells. When such cells enter the brain, they transform into just the types of cells thought to harbor the HIV reservoir.

The researchers also focused on a drug, phenelzine (Nardil), currently used to treat depression that doesn’t respond to other medications and able to enter the brain. Phenelzine stimulated HIV production from human microglial cells recovered from the brains of the HIV-infected humanized mice.

The authors felt that their model, and this new form of LRA, or latency reversing agent, shows “great promise as a model system for the development of strategies aimed at defining and reducing the central nervous system [brain] reservoir.”

Dr. Laurence is amfAR’s senior scientific consultant.

Gutting HIV

Very soon after an initial HIV infection, regardless of how it was acquired, HIV homes in on T cells in the gut. It establishes a latent HIV reservoir and, within days, disrupts the normal barrier between intestinal bacteria and the blood. These changes promote a state of chronic inflammation, which in turn fosters HIV growth and spread, and may accelerate disorders associated with aging of the heart, kidney and bone. Antiretroviral therapy (ART) may diminish, but does not stop, these processes.

 Dr. Peter Hunt and Dr. Steven Deeks

Dr. Peter Hunt and Dr. Steven Deeks

Writing in the March issue of the online journal PLoS Pathogens, Drs. Steven Deeks, Peter Hunt and associates from the amfAR Institute for HIV Cure Research at the University of California, San Francisco, and The Wistar Institute in Philadelphia, discovered a new link in this chain of events that may hold the key to promoting intestinal recovery in such individuals.

Using gut biopsies obtained from infected people taking ART, Deeks, Hunt and colleagues found higher levels of A20, a protein associated with reduced inflammation. In the gut biopsies of people not taking ART, on the other hand, A20 levels were reduced. The increase in A20 in those on ART was associated with an increase in three intestinal proteins that support healthy barrier functions of the gut.

But the link between A20 and gut integrity proved to be complex. Using a mouse model of the intestines—an “intestinoid” grown from gut cells in the test tube—they showed that A20 is critical for survival of those cells. But during untreated infection, A20 is suppressed by one element of the immune system’s response to the virus, namely interferon-alpha. The research team confirmed the link between interferon-alpha and A20 by studying the blood cells of HIV-infected individuals on ART who received additional treatment with interferon-alpha.  

Simply put, HIV infection increases the activity of interferon-alpha, which decreases A20 and thus causes harm. Conversely, antiretroviral therapy increases levels of A20, preventing the damage that would otherwise be done to cells in the gut.

The researchers concluded that “variation in A20 expression during the course of HIV infection could underlie both the development of [intestinal] epithelial dysfunction before the initiation of ART and the recovery of intestinal epithelial integrity thereafter…. Further studies are warranted.” Clearly they are, as this may be yet another part of the search for an HIV cure.

 

Dr. Laurence is amfAR’s senior scientific consultant.

 

Can "the Berlin Patient’s" Cure Be Replicated?

amfAR-funded European research consortium aims to find out

When the scientific community learned in a 2009 article in The New England Journal of Medicine that a man known as “the Berlin patient” had been cured of HIV, the news ushered in a new era of HIV research, one underpinned by the knowledge that curing HIV is possible.

But a single person represents an anecdote, and many questions remained unanswered. What are the best ways to measure a vanishingly small amount of virus to confirm that none remains? What were the key elements of his treatment that led to the cure? And most importantly, could this case be replicated?

  Co-Principal Investigators Drs. Javier Martinez-Picado (front right) and Annemarie Wensing (center right), pictured with ICISTEM members including Dr. Gero Hütter, “the Berlin patient’s” physician, and Dr. Maria Salgado. Also pictured are Dr. Rowena Johnston (front, second from right) and Dr. Jeffrey Laurence (back row, right) of amfAR. 

Co-Principal Investigators Drs. Javier Martinez-Picado (front right) and Annemarie Wensing (center right), pictured with ICISTEM members including Dr. Gero Hütter, “the Berlin patient’s” physician, and Dr. Maria Salgado. Also pictured are Dr. Rowena Johnston (front, second from right) and Dr. Jeffrey Laurence (back row, right) of amfAR. 

amfAR addressed the first question by bringing together a team of researchers to intensively study the blood and tissues of Timothy Brown, the Berlin patient, who has been remarkably generous with his body and his time in the service of science. We also brought together another team of researchers to compare every available assay that could quantify low levels of persistent viral reservoir.

amfAR subsequently funded three separate teams to more closely interrogate the circumstances and procedures that led to Timothy Brown’s cure. One of those researchers, Dr. Timothy Henrich, followed the two so-called “Boston patients,” who, after unusually long delays, experienced viral rebound, confirming that their transplants did not cure their HIV infection.

The groundbreaking work conducted by amfAR’s ICISTEM consortium has been recognized by two prestigious awards. Dr. Maria Salgado, a researcher from the IrsiCaixa AIDS Research Institute in Barcelona, Spain, was presented with the inaugural Dominique Dormont Award during the International ADIS Society Conference on HIV Science in Paris in July 2017. And Dr. Jon Badiola of the Virgen de las Nieves University Hospital in Granada, Spain, was presented with a Best Young Abstract Award at the Annual Meeting of the European Society for Blood and Marrow Transplantation in March 2018.

As ever in science, even disappointing results are an opportunity to learn new facts. Scientific findings were increasingly suggesting that the genetic mutation in the donor stem cells that Timothy Brown received were a vital, perhaps even foundational, element of his cure. Another grantee, Dr. Jonah Sacha, concluded that the rejection reaction of the transplanted cells against the recipient’s immune system (known as graft versus host disease) plays a central role in success against cancer and probably also HIV.

In 2012, amfAR began discussions with a group of European researchers with the goal of establishing a research consortium, now known as ICISTEM (www.icistem.org), that could take these questions even further. We chose Europe because it has the highest proportion of people living with the CCR5-delta32 genetic mutation that appears to have been central to Timothy Brown’s cure. The consortium is co-led by the IrsiCaixa AIDS Research Institute in Barcelona, Spain, and the University Medical Center Utrecht in the Netherlands. It includes HIV cure researchers, cancer transplant doctors, and doctors working to register stem cell donors and test their cells for the genetic mutation.

In January, amfAR met with the ICISTEM team in Berlin for an annual progress update and planning session. They have so far enrolled more than 30 patients with cancer and HIV who have received or soon will receive stem cell transplants. And they have identified over two million potential stem cell donors with the CCR5-delta32 mutation.

Most exciting, the group has conducted exhaustive testing for persistent reservoir in many of the transplanted participants and in several cases are unable to find evidence that any HIV remains. They are preparing to embark on the next phase of this scientific journey, the definitive test of a cure, namely the withdrawal of antiretroviral therapy. Results will take at least a year, and while we cannot promise that any of these people will be shown to be cured, we can promise that amfAR is pursuing every promising avenue to discover what it will take to finally cure HIV.

Dr. Johnston is an amfAR Vice President and Director of Research.

New Findings Point to Power of Antibodies

New research by amfAR grantee Dr. Dan Barouch and colleagues at Beth Israel Deaconess Medical Center in Boston further supports the idea that an HIV cure is likely to require a combination of agents rather than just one. It also offers further evidence of the potential role of antibodies in curing HIV.

 Dr. Dan Barouch

Dr. Dan Barouch

Barouch’s study involved a group of macaque monkeys infected with SHIV, a combination of HIV and SIV (the simian form of the virus). The researchers found that those monkeys that had been given a broadly neutralizing antibody called PGT121 combined with an immunotherapeutic drug that may act as a latency-reversing agent experienced a significant delay to viral rebound after being taken off antiretroviral treatment. They also rebounded to lower levels of virus. 

While the findings are extremely encouraging, the researchers cautioned that the results are very preliminary in relation to a cure for HIV. Dr. Barouch reported on his findings at the 2018 Conference on Retroviruses and Opportunistic Infections in Boston in February.

In a previous study reported in the August 2017 issue of the Journal of Virology, Dr. Barouch, along with colleagues from the Ragon Institute of MGH, MIT, and Harvard in Cambridge, MA, the National Institutes of Health in Bethesda, MD, and Leidos Biomedical Research and Frederick National Laboratory Center for Cancer Research in Frederick, MD, used a “passive immunization” approach to explore the potential role of antibodies in curing HIV infection.

This study also involved monkeys infected with SHIV. The monkeys were treated with either PGT121 or another antibody know to have anti-HIV properties called N6, a combination of both, or a placebo. The antibodies reduced the viral load in the monkeys.

The researchers then measured SHIV DNA in the blood and lymph nodes to see if the antibodies had any effect on infected cells. They found significantly reduced levels of SHIV DNA in the blood two weeks after the antibodies were administered; in the lymph nodes, SHIV DNA dropped markedly after 10 weeks.

These results suggest that passive immunization using these antibodies might, under the right conditions, kill cells of the persistent viral reservoir and thus play a role in curing HIV.

A Potential New Target for Eradication of HIV Reservoirs

In the January update we featured research led by amfAR-funded scientists at Case Western Reserve University on an FDA-approved drug, ruxolitinib, used in the experimental treatment of lymphoma. Writing in the February issue of the journal PLoS Pathogens, Drs. Timothy Henrich and colleagues at the amfAR Institute for HIV Cure Research at the University of California, San Francisco, and at Harvard University, continue this concept of evaluating anti-cancer drugs in anti-HIV strategies.  

 Dr. Timothy Henrich

Dr. Timothy Henrich

The investigators studied the FDA-approved drug brentuximab (Adcetris). It is a toxin linked to a monoclonal antibody in order to target the activity of that toxin to cells that express the molecule CD30 on their surface. The drug is an important part of the treatment of resistant Hodgkin disease, a type of cancer, and certain other types of aggressive lymphoma. Fortunately, its target is highly expressed on certain tumor cells, but on only a very small percentage of normal cells. Dr. Henrich and his colleagues took advantage of the fact that other researchers had reported high levels of CD30 in patients with untreated HIV infection.

Henrich and colleagues now document that HIV is highly enriched in CD4+ T cells expressing CD30 obtained from HIV-infected individuals, regardless of whether or not they are on suppressive antiretroviral therapy (ART). Furthermore, exposure of T lymphocytes obtained from these individuals to brentuximab in the test tube reduces the amount of HIV DNA—a measure of virus reservoir size.

Their studies also addressed the question of HIV reservoirs in tissue. Active HIV in gut samples obtained from some of the patients was concentrated in CD30 positive cells.

Bringing this research back to the patient, the investigators studied an HIV-infected individual given brentuximab for his lymphoma. He had no detectable virus in his blood after six cycles of treatment. This was unexpected, as HIV-infected individuals receiving other types of chemotherapy do not lack detectable HIV. Although brentuximab has serious side effects and must be given as an intravenous infusion, limiting its applicability for HIV-positive individuals who don’t require it for cancer treatment, the authors rightly conclude that “CD30 is a potential therapeutic target of persistent HIV-1 infection.”  


Dr. Laurence is amfAR’s senior scientific consultant.

Progress Toward a Better “Shock and Kill”?

amfAR-funded scientist Dr. Brad Jones of George Washington University in Washington, DC, has discovered an obstacle to the “shock and kill” strategy for curing HIV that may have implications for the success of this approach in the clinic.

“Shock and kill” involves using drugs to “shock” latent virus out of hiding so that it can be killed by the immune system or interventions such as a therapeutic vaccine or broadly neutralizing antibodies. In the February issue of The Journal of Clinical Investigation, Jones and colleagues report that the latent HIV reservoir resists attack by CD8 T cells, immune cells charged with clearing virally infected cells.

 Dr. Brad Jones

Dr. Brad Jones

The authors note that shortly after a person becomes infected, HIV begins to accumulate mutations. As a result, over 88% of viral genes are so defective they are unable to produce infectious virus. However, the reservoir makes up a tiny fraction of the remaining 12% of infected cells and harbors intact genomes capable of producing infectious virus.

Previous ”shock and kill” strategies aimed to reawaken this latent reservoir with drugs called latency-reversing agents (LRAs) to expose the infected cells to the killing power of the immune system. (View amfAR’s explanatory video here.) However, Jones’s research shows that even after reactivation of the reservoir, CD8 T cells prefer to kill cells infected with defective virus and thus have little effect on the reservoir. Even more intriguing, the scientists found evidence to suggest that the reservoir cells, when attacked by CD8 T cells, somehow shield themselves from their deadly onslaught.

At a December scientific conference in Miami, Jones presented related findings pointing to a drug that could make the reservoir more susceptible to killing in a “shock and kill” context. In this “prime, shock and kill” strategy, a drug is given to the patient to prime, or prepare, the reservoir to submit to being killed by CD8 T cells. Then, just as with “shock and kill,” LRAs are added to reawaken the reservoir and mark those cells for killing by the immune system.

“Overall,” Jones said, “I remain very optimistic about “shock and kill” … I just think we may be missing an extra piece of the puzzle. We may have more success with ‘prime, shock and kill.’”

While more work needs to be done to improve “shock and kill,” such as developing more potent LRAs, Jones’s findings could help improve the effectiveness of this strategy.

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

amfAR Renews Investment in Bioengineering Approaches to Curing HIV

amfAR, The Foundation for AIDS Research, today announced a pair of research grants that renew its support for innovative approaches to HIV cure research. Totaling nearly $1 million, the Investment grants will allow two collaborative teams of HIV researchers and bioengineers to embark on a second phase of projects initiated with amfAR funding awarded in February 2017. 

Transmitting HIV (in the Test Tube) Despite Antiretroviral Therapy

During initial infection with HIV from anal or vaginal intercourse, a type of immune cell known as a dendritic cell (DC) is the first component of the immune system to encounter the virus at mucosal surfaces. Such surfaces protect the body from viruses and bacteria. DCs can migrate to lymph nodes and similar tissues, where contact with T cells may then play a key role in spreading the virus. This process, known as “trans infection,” occurs despite the fact that DCs themselves cannot be directly infected with HIV.

 Dr. David Baltimore

Dr. David Baltimore

In the January issue of the journal PLOS ONE, amfAR grantee and Nobel Prize laureate Dr. David Baltimore of Caltech in Pasadena, CA, with colleagues from the University of California, Los Angeles, the Max Planck Institute for Infection Biology in Berlin, and the Africa Health Research Institute in Durban, South Africa, examines this process in the test tube.

The investigators found that DCs can transmit HIV to T cells by direct contact despite the presence of two very potent anti-HIV drugs: the reverse transcriptase inhibitor tenofovir and the integrase inhibitor raltegravir. This was dependent on the number of DCs contacting a T cell and the amount of virus present in the body.

Researchers also discovered that DCs may increase the probability of establishing an HIV infection not only by transporting the virus, but also by amplifying the number of cells it can infect. DCs also reduce the anti-HIV potency of drugs. The latter is of particular concern in lymph nodes, which may have lower drug levels than in the blood and other tissues. It also has implications for HIV cure strategies.

The authors conclude: “Transmission of HIV by DCs in trans may have important implications for viral persistence in vivo in environments where residual replication may persist in the face of antiretroviral therapy.”

Dr. Laurence is amfAR’s senior scientific consultant. 

Cancer Drug Leads to ‘Drastic Decrease’ of HIV Reservoir in Patient

A team of French doctors observed a “drastic and persistent decrease” of the HIV reservoir in a lung cancer patient given a drug commonly used to treat several cancers in their advanced stages.

The reservoir is the collection of HIV-infected cells that persists despite antiretroviral drugs and hides under the radar of the immune system. It is the wellspring of HIV that quickly rebounds when treatment is stopped.

“This is the first case of such a drastic decrease of the HIV reservoir,” said Dr. Jean-Philippe Spano, head of the medical oncology department at Pitié-Salpêtrière Hospital in Paris where the patient was treated. But, he cautioned, “we must remain careful, especially because this is only one case.” Spano and his colleagues detailed the case last month in a letter published in Annals of Oncology.

 Dr. Jean-Philippe Spano

Dr. Jean-Philippe Spano

The 51-year-old man was given nivolumab (marketed as Opdivo) once every two weeks starting in December 2016 after he relapsed following surgery and chemotherapy for his tumor. Nivolumab has been shown to be effective in treating melanoma, non-small cell lung cancer, and kidney cancer.

When the patient started treatment, his viral load was undetectable. It steadily climbed until day 45 before falling again. During that time, the activity of his T cells also increased. By day 120, he had experienced "a drastic and persistent decrease" in HIV reservoir levels, the researchers said.

Doctors believe the cancer drug may have enhanced the “killing” of HIV-infected cells by releasing the brakes the immune system deploys for safety. However, they noted that another HIV-infected patient given the same treatment did not experience a reduction in the reservoir.

Still, the findings “could have implications for HIV patients, both with and without cancer, as it can work on HIV reservoirs and tumor cells independently," Spano said. “The absence of side effects in this patient is also good news and suggests this could be an optimum treatment for HIV-infected patients with cancer."

Commenting on the study for HealthDay, Dr. Marcella Flores, amfAR’s associate director of research, called the case “interesting and hopeful.” However, she noted that while the drug caused a substantial decrease of the HIV reservoir, it did not completely eradicate the virus.

She told the news service that more work needs to be done to better understand this particular patient's experience and to figure out how it might help others.

See also: https://www.sciencedaily.com/releases/2017/11/171130214929.htm

amfAR-Funded Researchers Look to Antibodies to Cure HIV

Killing HIV reservoir cells—cells that are persistently infected with the virus—would potentially eradicate HIV from the body. In three journal articles published in December, amfAR-funded scientists discuss recent advances in understanding how immune system cells use antibodies to kill HIV-infected cells via antibody-dependent cellular cytotoxicity (ADCC). ADCC is an immune response in which antibodies act as homing devices to recruit immune cells that target and kill infected cells.

 Dr. Amy Chung

Dr. Amy Chung

These advances include: developing tools to better understand antibody functionality; identifying which antibodies are most suited to ADCC; and examining their protective role against infection.

The goal: to learn how antibodies can cure HIV.

A new tool to examine antibody function

In a study published in the journal Retrovirology, amfAR-funded scientists Drs. Amy Chung of the University of Melbourne in Australia and Galit Alter of the Ragon Institute of MGH, MIT and Harvard University in Cambridge, MA, write about a platform of techniques called systems serology, which they developed to explore the functionality of antibodies. Through this approach, which uses machine learning algorithms to analyze data on the biophysical and functional properties of antibodies, Chung and Alter can identify features of HIV-specific antibodies that are better able to engage in ADCC. They hope that by using systems serology in primate vaccine studies, they can better understand how vaccines skew immune responses to protect against infection or how to improve the ADCC response in humans.

Antibodies protect non-HIV infected partners

 Dr. Galit Alter.jpg

Dr. Galit Alter.jpg

Supported by an amfAR Mathilde Krim Fellowship, Chung is studying the mechanisms of interaction between vaccines that produce IgA, a type of antibody present only in mucosal tissues, and IgG, an antibody present in the blood, to provide partial protection against HIV. Writing in the journal EBioMedicine, she comments on a study carried out by researchers at the University of Buenos Aires in Argentina that supports her observations: the ratio of IgG to IgA correlates with the killing action of antibodies, most likely through ADCC. Furthermore, HIV-infected persons with high ratios of IgG to IgA are much less likely to transmit the virus to their HIV-free partners. She concludes that even people not infected with HIV benefit from their HIV-positive partners’ effective antibody responses.

A narrow window for antibody susceptibility in HIV-infected cells

 Dr. Andrés Finzi

Dr. Andrés Finzi

And in a third study published in the journal Virology, amfAR-funded scientist Dr. Andrés Finzi of the Centre de Recherche du CHUM in Montreal, reports on the susceptibility of the viral protein Env—present on the surface of actively infected cells—to antibodies. Finzi shows that Env exists in three different states: open, partially open, and closed. It had previously been thought that Env was only vulnerable to antibody attack in the open position. However, by altering the protein to lock it into a partially open position, Finzi found that it, too, was subject to antibody binding. Through this finding, Finzi has increased the options researchers have for designing antibodies to target Env and eventually eliminate HIV-infected cells through ADCC.

In conclusion, all three of these studies will provide us with the tools and knowledge we need to manipulate immune responses to harness the killing power of antibodies and cure HIV.

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

 

Cancer Gene Therapy Strategy Suppresses HIV in Lab Study

The first FDA-approved gene therapy treatment for cancer patients has shown promise in suppressing HIV infection long term in lab monkeys, according to a study partially funded by amfAR.

Researchers genetically engineered stem cells to express chimeric antigen receptors (CAR) that can detect and destroy SHIV (a combination of HIV and SIV—the monkey form of the virus). The cells were then tested in four male juvenile SHIV-infected macaques.

 Dr. Scott Kitchen

Dr. Scott Kitchen

Not only did the engineered cells decrease the viral load, they persisted for more than two years in the monkeys without any adverse effects. Furthermore, the cells were widely distributed throughout the lymph nodes and gastrointestinal tract, where viral replication and persistence are concentrated.

“The advantage of the stem cell-based approach is that once these cells are grafted into the body, they continuously produce new T cells that have this gene in them that can target HIV cells,” said amfAR grantee Dr. Scott Kitchen of the University of California, Los Angeles.

The FDA approved the gene therapy treatment Kymriah in August 2017 for young people up to age 25 with a form of acute lymphoblastic leukemia, a blood cancer. The therapy involves modifying a patient’s own T cells and genetically engineering them with CAR cells that can recognize and kill tumors.

Its approval coincided with the announcement of two amfAR grants exploring a similar strategy to curing HIV.

Commenting on the study for HealthDay, Dr. Marcella Flores, amfAR’s associate director of research, said she was cautiously optimistic about the potential of gene therapy to eradicate the virus. “CAR therapy is already leading to impressive results in cancer,” she said.

However, she noted that the study was performed in monkeys. Results in humans may be quite different.

Kitchen said human trials could begin within two to three years. While it is unlikely that the CAR strategy will work completely on its own, he said it could be used with antiretroviral therapy to engineer an immune response to target and kill HIV.

“Theoretically the goal is to provide lifelong immunity to HIV,” he said. “We’re aiming for a cure, and we know that to cure HIV you need an effective immune response.”

The study was published in the December 28 issue of PLOS Pathogens.

See also: Using Groundbreaking CAR-T Cancer Therapy to Eliminate HIV

Novel Methods to Eradicate HIV Reservoirs

In a summer update, we highlighted research from the amfAR Institute for HIV Cure Research at the University of California, San Francisco, involving a drug developed to fight cancer in a “shock and kill” approach to curing HIV. The authors concluded that findings from such a line of research underscore “the emerging ties between cancer and HIV treatment through shared drug targets.”

 Dr. Cheryl Cameron

Dr. Cheryl Cameron

Now in an article in the December 2017 issue of PLoS Pathogens, amfAR-funded scientists Drs. Cheryl Cameron from Case Western Reserve University in Cleveland and Franck Dupuy from McGill University in Montreal, with colleagues from both institutions, Emory University in Atlanta—including amfAR board member Dr. Raymond Schinazi—and the University of Montreal, explore using other drugs approved to treat other diseases to eradicate HIV.

The investigators studied two FDA-approved drugs, ruxolitinib, used to treat a bone marrow disorder known as myelofibrosis and some cases of lymphoma, and tofacitinib, used to treat rheumatoid arthritis and inflammatory bowel disease. These agents share a mechanism of action: inhibition of a normal cell protein known as Jak, a key promoter of inflammation.

 Dr. Franck Dupuy

Dr. Franck Dupuy

In test tube studies, the researchers used concentrations of the two drugs that are typically found in the blood of the patients taking them. They were able to block HIV production from infected T cells, inhibit activation of the virus from latently infected cells, and reduce the number of latently infected cells in HIV-infected individuals on antiretroviral therapy. This was accomplished without suppressing immune function.

The authors concluded: “Jak inhibitors represent a potential therapeutic modality that addresses a clinical need which traditional direct-acting antiviral agents that interfere with steps in the viral replication cycle have not been successful.”

Indeed, the role of ruxolitinib in reducing inflammation associated with HIV infection is currently being evaluated in a National Institutes of Health-funded clinical trial. Inflammation is believed to contribute to the persistent HIV reservoir, the primary barrier to a cure.

Dr. Laurence is amfAR’s senior scientific consultant. 

A New Model to Explore Stem Cell Transplantation Approaches to an HIV Cure

A New Model to Explore Stem Cell Transplantation Approaches to an HIV Cure

hus far, there is but a single example of a human cured of HIV: the “Berlin patient,” whose HIV was eradicated following a hematopoietic stem cell transplant (HSCT) from a donor with a rare genetic mutation (CCR5-delta 32) conferring resistance to HIV infection.