Uncovering Novel Anti-HIV Factors

Research Question

Elite controllers, capable of suppressing HIV replication in the absence of antiretroviral therapy (ART), represent less than 1% of all HIV-positive individuals. While small in number, their participation in research studies has been critical to our understanding of how a functional cure for HIV might be achieved. Furthermore, while most studies of elite controllers have used peripheral blood, HIV growth occurs primarily in lymph nodes, raising the question: How might cells in those immune tissues contribute to viral suppression?

Dr. Steven Deeks

Findings

amfAR-funded researchers investigated immune cells obtained from the lymph nodes of elite controllers. They compared them to cells obtained from “chronic progressors,” who are individuals with advancing HIV disease in the absence of ART. They found that CD8+ T cells—usually thought of as virus “killers”—isolated from elite controllers suppressed HIV replication without killing infected cells. This activity was associated with producing and releasing substances such as immune hormones or cytokines.

Researchers then investigated the range of cytokines each CD8+ T cell was capable of making in response to HIV. Cells that can make many different types of immune enhancing cytokines might be better able to suppress HIV than cells that make only one or two types.

Consistent with this assumption, researchers found that the cells of elite controllers were more likely than those of chronic progressors or HIV-positive individuals on ART to produce a wider range of cytokines. In fact, only CD8+ T cells from elite controllers were capable of making up to five different types of cytokines.

Impact

The authors argue that this finding is “highly pertinent” to guiding the search for a functional cure—achieving remission—of HIV. These investigations primarily focus on kill strategies, but should also consider antiviral factors, which suppress rather than kill the virus.

amfAR’s Role

Dr. Steven Deeks, a co-author of the study, is a member of the amfAR Institute for HIV Cure Research at the University of California, San Francisco.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/31852798

Dr. Laurence is amfAR’s senior scientific consultant.

Uncovering an Early Marker for HIV Reactivation

Research Question

HIV-positive individuals involved in cure studies typically agree to stop antiretroviral therapy (ART) as part of an analytic treatment interruption (ATI) so that scientists can gauge the efficacy of a particular intervention. Identification of markers predictive of HIV reactivation following interruption of ART would be of enormous benefit to HIV cure research.

Findings

amfAR-funded researchers and their colleagues studied 23 individuals from five different clinical trials that included an ATI component. Changes in a subset of CD4+ T cells in the blood—those carrying a surface protein known as CD30, a marker of certain activated T cells—were measured starting two weeks after interruption of ART. The frequency of cells containing the CD30 marker increased almost twofold in three-quarters of the 23 individuals. These changes preceded detection of the virus itself and, in some cases, occurred up to a month before clinically apparent HIV rebound.

Impact

There are valid concerns about the safety of interrupting ART, given the uncertain risks of viral rebound. This study found that CD30 may provide a tool both for accessing important research information—using biopsies or scans to identify those parts of the body from which the virus first reappears—and to permit restarting ART before HIV becomes detectable in the blood.

amfAR’s Role

Researchers involved with this study are affiliated with the amfAR Institute for HIV Cure Research.

Original Article
http://www.ncbi.nlm.nih.gov/pubmed/31677350

Dr. Laurence is amfAR’s senior scientific consultant.

amfAR Awards Support Promising Young HIV Researchers

Krim Fellowships cultivate new scientific talent with fresh
approaches to HIV/AIDS research

NEW YORK, Dec. 5 2019 --- amfAR, The Foundation for AIDS Research, has announced the 2019 recipients of the Mathilde Krim Fellowship in Basic Biomedical Research. Named in honor of amfAR Founding Chairman Dr. Mathilde Krim, the Krim Fellowship program supports early career scientists pursuing innovative solutions to HIV/AIDS. The two Krim Fellows – Maolin Lu, Ph.D., at Yale University, New Haven, CT, and Shaheed Abdulhaqq, Ph.D., at Oregon Health and Science University, Portland, OR – will each be awarded $150,000 over two years.
“Through the Mathilde Krim Fellowships, amfAR has committed more than $8 million since 2008 to support the development and the work of outstanding young HIV/AIDS researchers,” said Kevin Robert Frost, amfAR’s Chief Executive Officer. “These annual awards enable us to continually infuse the field with youthful vigor, exceptional talent, and new ideas.”

Dr. Lu is a structural biologist and a recognized expert in the use of state-of-the-art imaging techniques that can interrogate single molecules. Dr. Lu recently published a groundbreaking study in Nature that upended the HIV vaccine field. Previously, vaccinologists had used a lab-made version of the HIV envelope protein, Env, to produce broadly neutralizing antibodies that could prevent or treat HIV infection. Using these imaging techniques, including fluorescent signals to detect the proximity of nearby molecules, Dr. Lu was able to show that this version of Env wasn’t an accurate model after all. 

Working under her mentor Dr. Walther Mothes, she will build on her study to map the exact sequence of structural changes when Env fuses to a target cell. Understanding how these proteins on the HIV surface change upon encountering host cells may advance the development of powerful new broadly neutralizing antibodies and antiretroviral therapies.

Dr. Abdulhaqq, working in the lab of his mentor Dr. Jonah Sacha, is testing a hypothesis that may have implications for an HIV cure. A 2011 study of a vaccine administered before infection found that more than half of the study animals infected with the HIV-like virus SIV eventually cleared the virus. However, there was no protection if the vaccine was given only after infection. 
Dr. Abdulhaqq will investigate what prevents vaccine-induced immune cells called CD 8 T cells from being effective therapeutically once infection has been established. He hypothesizes that vaccine-induced T cells for prevention targeted the gut, whereas they need to target persistent reservoirs of HIV in other tissues in order to have a therapeutic effect. Using a gene therapy approach, he plans to modify CD8 T cells to make them like vaccine-induced cells and direct them, with the addition of a homing protein, to the HIV reservoirs where infected cells hide.

“The Mathilde Krim Fellowships in Basic Biomedical Research are an important and enduring legacy of amfAR’s Founding Chairman,” said Dr. Rowena Johnston, amfAR vice president and director of research. “Through these awards, we remain committed to identifying and supporting talented early career scientists who have the skills and vision to lead us to new breakthroughs and further progress toward ending the AIDS epidemic.”

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 advocacy. Since 1985, amfAR has invested nearly $550 million in its programs and has awarded more than 3,300 grants to research teams worldwide.

2019 HIV Cure Summit

A World AIDS Day Community Update on HIV Cure Research

Biomedical researchers, clinicians, and community leaders were among those presenting various perspectives at amfAR’s 2019 World AIDS Day HIV Cure Summit at the University of California, San Francisco (UCSF), on November 21. UCSF is home to the amfAR Institute for HIV Cure Research, established in 2015 with a five-year $20 million grant. Approximately 200 people attended the community update, which featured talks by leading experts in HIV cure research and members of the amfAR Institute for HIV Cure Research community advisory board.

THURSDAY, NOVEMBER 21
1:00 – 4:00 P.M. Cure Summit 
4:00 – 5:00 P.M.  Reception  

Robertson Auditorium
UCSF Mission Bay Campus
1675 Owens Street
San Francisco

Participants included:

Matthew Chappell, LCSW, ACM-SW
Manager, Care Coordination, Stanford Health Care
amfAR Institute for HIV Cure Research CAB

Steven G. Deeks, M.D.
Professor of Medicine
UCSF

Marcella Flores, M.P.H., Ph.D.
Associate Director of Research
amfAR, The Foundation for AIDS Research

Peter Hunt, M.D.
Associate Professor, Division of Experimental Medicine, UCSF
Co-Director, UCSF-GIVI Center for AIDS Research for Basic and Translational Science
   
Keith Jerome, M.D., Ph.D.
Professor of Laboratory Medicine and Head, Virology Division
University of Washington

Rowena Johnston, Ph.D.
Vice President and Director of Research
amfAR, The Foundation for AIDS Research

Satish Pillai, Ph.D.
Senior Investigator, Vitalant Research Institute
Associate Professor of Laboratory Medicine, UCSF

Rachel Rutishauser, M.D., Ph.D.
Assistant Professor of Medicine
Division of Experimental Medicine, UCSF

Paul A. Volberding, M.D.
Professor Emeritus of Medicine, UCSF
Director, UCSF AIDS Research Institute
Director, amfAR Institute for HIV Cure Research

Loreen Willenberg
HIV Community Advocate
Founder and Executive Director
Zephyr LTNP Foundation

#CureAIDS

New amfAR Grants Advance HIV Cure and Post-Treatment Control Studies

Awards totaling $1.16 million will support ‘Trojan horse’ approach to curing HIV
and effort to unlock the secrets of post-treatment control

NEW YORK CITY, August 27, 2019 — Through the amfAR Research Consortium on HIV Eradication (ARCHE), a grant program that fosters collaboration among teams of scientists, amfAR has awarded new grants totaling $1.16 million to advance a pair of innovative research studies attacking HIV from very different angles.   

Keith Jerome, Ph.D., of the University of Washington, Seattle, was awarded $344,000 for a project that aims to advance a gene therapy strategy for curing HIV. Gene therapy is emerging as one of the most promising interventions across all of biomedical science, including HIV, but it carries a number of risks and challenges. Scientists need to find ways to improve the efficiency of appropriately altering DNA, effectively target the correct cells, and enable the therapy to safely persist long enough to have an effect.

Moreover, a substantial limitation of current approaches is their cost in the clinic, which can be as much as $2 million or more. amfAR’s ARCHE-GT consortium plans to reduce costs by developing in vivo gene therapy in which the gene-engineering tools are injected directly into the patient. These tools are delivered inside vectors, which function as ‘Trojan horses.’

Dr. Jerome’s team plans to compare which of 11 vectors delivers the gene-editing tools most effectively to the various specific tissues that are being targeted. These lead candidates will then be used in future studies of combination in vivo gene therapy interventions.

Another area of HIV research in which amfAR is particularly interested is post-treatment control. Post-treatment controllers (PTCs) are HIV-positive individuals who, unlike the majority of people living with HIV, are able to control their virus after stopping antiretroviral therapy (ART). But discovering the mechanisms of this control has proven difficult since the rarity of PTCs has so far precluded analysis of a sufficient number of samples.

amfAR’s ARCHE-PTC collaboration consists of the world’s leading experts in PTC research and brings together clinical cohorts of PTCs from all over the world, including an all-female cohort from Cameroon, under one streamlined analysis plan. Dr. Jonathan Li of Brigham and Women's Hospital in Boston has assembled an impressive cohort of post-treatment controllers from one of the largest HIV clinical trial networks in the world.

Supported by an amfAR grant of $815,000, Dr Li and his team will gather and analyze samples from this multinational PTC cohort and will be able to employ cutting-edge tools to investigate whether characteristics of the virus or immunologic responses can predict post-treatment control. Discovering what leads to post-treatment control in some people could help to achieve durable ART-free control in all people living with HIV.

“We’re excited to be supporting these immensely talented research teams and their very different but very promising avenues of investigation,” said Dr. Rowena Johnston, amfAR vice president and director of research. “These research areas have enormous potential for giving us the tools to control the virus without the need for lifelong treatment or, in the case of gene therapy, to eliminate it altogether. Either outcome could dramatically alter the lives of the millions of people living with HIV worldwide.”

Former Krim Fellow Wins Prestigious NIH Award

Dr. Alon Herschhorn

Dr. Alon Herschhorn is an Assistant Professor of Medicine in the Division of Infectious Diseases and International Medicine at the University of Minnesota. He has previously held a faculty position and conducted research at the Dana-Farber Cancer Institute and Harvard Medical School, and is the recipient of a Rothschild Fellowship and an amfAR Mathilde Krim Fellowship in Basic Biomedical Research. Dr. Herschhorn has now won a 2019 Avenir Award for HIV/AIDS Research for a project investigating the pathways used by HIV to escape broadly neutralizing antibodies. He is also building a platform to bioengineer a vaccine able to more precisely target the HIV envelope proteins (Env) for elicitation of broadly neutralizing antibodies. Dr. Herschhorn hopes that his in vitro and in vivo studies will lead the way to new therapeutic and preventive strategies against HIV.

amfAR: How did you become interested in HIV research?

Dr. Herschhorn: When I started my undergraduate studies, I was looking for a challenging research direction that would be both important and have an impact on human health. At that time, there were only a few FDA-approved drugs for antiretroviral therapy, and HIV quasispecies—“swarms” of mutated viruses—in patients were rapidly developing resistance to these drugs. The HIV pandemic was spreading at an alarming rate and there were emerging efforts to prevent transmission.

These were difficult times and I thought that understanding the complex biological processes involved in the HIV life cycle would provide insights and tools for developing new strategies for interventions. I started working on two HIV enzymes: reverse transcriptase and integrase, which are main targets of antiretroviral drugs. Then, during my postdoctoral studies, I focused on the molecular mechanisms of Env function, which is key to the development of an effective HIV vaccine.  

I would like to add that I was lucky to be able to do what I love through my career and encourage researchers starting their scientific journeys to trust their hearts to do what they really love. Everything else will follow.

amfAR: It is often difficult for early career scientists to find funding. How did our Mathilde Krim Fellowship help to advance your research career?

Dr. Herschhorn: I will always be grateful to the Mathilde Krim Fellowship for advancing my research career. The prestigious fellowship was not only an acknowledgment of my past scientific achievements and vision for the future, but it was the first time that I learned how to responsibly manage a budget for a scientific project, how to interact with a program administrator, and how to apply for NIH funding after participating in a workshop on the NIH grant mechanisms.

The second phase of the Krim Fellowship was critical. At that time, funding in our laboratory was rapidly decreasing and my visa status depended on a sponsor. Without the support of amfAR funds, I probably would have had to leave the U.S. and start over. Luckily, the second phase of funding provided me extra time and support to continue my studies and I laid new groundwork for understanding HIV Env function and inhibition. These concepts opened new opportunities for research and were the basis of my successful application for the Avenir Award (NIH Director's New Innovator Award mechanism) from the National Institute on Drug Abuse. I would like to personally thank Jonathan Miller and Dr. Marcella Flores for their help during the grant period. 

amfAR: Can you summarize your work since completing the Mathilde Krim Fellowship?

Dr. Herschhorn: The Krim Fellowship provided me with the time and support to establish a new platform for dissecting HIV Env function. After completing the fellowship, I used these tools to study the molecular mechanisms of HIV entry into the cell. In collaboration with the groups of Dr. Walther Mothes of the Yale School of Medicine and Dr. Peter Kwong of the NIH, we identified a switch that regulates changes in the structure of HIV Env during cell entry. We showed that the regulatory switch controls opening of HIV Env from a closed to a more open conformation during the interactions with the CD4 cellular receptor.

I have also developed a new system to monitor HIV latency and replication at single cell and population levels. The system, which is based on concepts published by the group of Dr. Eric Verdin of the University of California, San Francisco, was distributed to more than ten laboratories around the world and is now being used as part of scientific collaborations to understand the alternative outcomes (viral latency or active replication) of HIV infection in target cells.

Since my appointment as Assistant Professor at the University of Minnesota, I have been applying the knowledge and tools that I developed during and after the Krim Fellowship to bioengineer new Env-based immunogens for HIV vaccine development, to delineate the pathways used by HIV to escape broadly neutralizing antibodies—specialized antibodies able to inactivate diverse types of HIV—and to elucidate the network of HIV-host interactions during HIV infection.

amfAR: What are your hopes for the HIV research field in the next five years?

Dr. Herschhorn: There are several exciting research directions that may lead to insights into the interactions of HIV with the immune system and HIV pathogenesis.

Multiple clinical trials are now testing the effect of administration of broadly neutralizing antibodies to people who live with HIV. Evidence from a minority of patients suggests that, in a few cases, HIV may be suppressed for a long period of time. I hope that in the next five years we will understand why these antibodies have long-lasting effects in some patients, how long HIV can be suppressed, and the limitations of the ability of HIV to develop resistance in vivo.  

Several vaccine trials have begun. One design will test the ability of a germline-targeting immunogen to elicit broadly neutralizing antibodies specific to the CD4 binding site of HIV Env. I hope that the results of this trial will guide new strategies to elicit broadly neutralizing antibodies in humans.

We need a method for robust measurement of the latent, replication competent reservoir (of HIV with all the components needed to assemble virions) in infected individuals. I hope that advances in next generation technologies will lead to a simple assay capable of measuring the size of the replication competent HIV reservoir in patients.

As a final comment, I would like to say that I am grateful to many people that helped me along the way: Drs. Ashley Haase, Timothy Schacker, and Reuben Harris, who provided endless support since my arrival to the University of Minnesota; Dr. Joseph Sodroski, my postdoctoral mentor at Harvard Medical School and Dana-Farber Cancer Institute; Dr. Alan Engelman, who offered me a short-term position when I most needed one, Dr. Walther Mothes for the continuous support, and Dr. Amnon Hizi, my adviser during my graduate studies.

Designing a Better Model for HIV Infection

Background

Dr. Amit Sharma

Monkey models are critical to exploring almost everything related to human HIV-1 infection, from vaccines to treatment and cure. But HIV-1 does not persistently infect the small monkeys known as macaques available for studies. Instead, these primates are susceptible to SIV—an HIV-like virus that can cause AIDS in monkeys.

Researchers study macaques infected with SHIVs—a combination of SIV and HIV—which resemble the activity of HIV in a monkey. But SHIVs have a limitation: They don’t grow well in monkey cells, partly because the viral envelope triggers production of interferons—proteins produced by the body shortly after infection that serve as a main defense against many viruses.

The Research Question

In this study, the challenge was to identify the factors involved in interferon-based limits to growth of SHIVs.

Findings

Researchers used a technique known as RNA-Seq to capture all the genes activated by interferon in macaque immune cells. By examining the proteins produced by those genes they could home in on those most likely to interfere with the HIV envelope—the viral culprit known to result in interferon production.

They identified several interferon-induced transmembrane (IFITM) proteins, which are present in macaques but not in humans. Scientists used CRISPR-Cas9 technology (a gene-editing tool) to delete IFITMs in monkey cells and saw that SHIV could grow, even in the presence of interferon. These findings confirmed that it was the IFITMs—activated by interferon—that prevented SHIVs from growing well in monkey cells.

Impact

The authors note that the study “may shed light on new approaches to improve the SHIV/macaque models by rationally designing SHIVs while maintaining as much as possible of the HIV-1 character of the virus.” It may also help to define how other viruses adapt to host restriction factors, enabling transmission across species.

amfAR’s Role

Dr. Amit Sharma is an Assistant Professor at Ohio State University and is funded by amfAR.

Original Article

http://www.ncbi.nlm.nih.gov/pubmed/31260493

Dr. Laurence is amfAR’s senior scientific consultant.

amfAR Second Largest Funder of HIV Cure Research

Modest global HIV cure funding increases sustained in 2018

In a new report, amfAR has been named the second largest HIV cure research funder in the world—second only to the U.S. National Institutes of Health. Released at the 10th IAS Conference on HIV Science in Mexico City, Global Investment in HIV Cure Research and Development in 2018 shows total global investments continuing to steadily increase.

The report—compiled by the Cure Resource Tracking Group, a collaboration between AVAC and the International AIDS Society—estimates global investments in HIV cure research of $323.9 million in 2018, a 12 percent increase over the $288.8 million invested in 2017. Compared to the $88.1 million invested since tracking began in 2012, this is a 268 percent increase.

The public sector accounted for the majority of funding, with the remaining $19.7 million invested by philanthropies. amfAR accounted for more than half of all philanthropic investment, with $10.9 million in funding last year.

“amfAR is proud to be recognized for its commitment to HIV cure research,” said Dr. Rowena Johnston, amfAR Vice President and Director of Research. “We remain steadfast in our pursuit of the most innovative and promising paths toward a cure.”

“The inclusion of ‘cure’ in the global response should not direct funding away from treatment, prevention and care programmes, or from biomedical research on HIV and its consequences, including vaccine and other prevention research,” noted the report’s authors. “However, it is imperative that donors, governments and the AIDS community make a viable and sustained economic investment in HIV cure research.”

Read the full report here.

How HIV Hijacks Cell Machinery

Background

Dr. Jonathan Richard

For nearly half a billion years, retroviruses and the animal immune systems they infect have each evolved strategies to outmaneuver the other in a kind of molecular arms race. HIV—which crossed into humans in the early 1900s—has inherited and advanced the strategies of its retrovirus predecessors.

HIV uses the molecular machinery inside the host cell to replicate. Studying interactions between the viral and host proteins reveals mechanisms of infection including viral replication, the host response, and how the virus eludes that response.

The Research Question

In two new studies, amfAR-funded researchers reported on methods used by HIV to impede immune defenses. In one study, Dr. Jonathan Richard of Université de Montréal, Centre de Recherche du CHUM and colleagues investigated how a viral protein targeted multiple cellular defenses at once. In another study, Dr. Judd Hultquist of Northwestern University School of Medicine and colleagues investigated how the virus “hijacked” host proteins involved in an antiviral defense pathway.

Dr. Judd Hultquist

Findings

HIV virions bud from the cell membrane and then travel to infect a new cell. The host protein BST-2, or tetherin, defends against budding by tethering virions to the cell membrane. In response, HIV uses its viral protein Vpu to prevent BST-2 from tying down the emerging virion.

Vpu also thwarts another host defense: the recognition and killing of infected cells by natural killer (NK) cells. Dr. Richard and colleagues reported that the drug interferon alpha (IFNa) increased the amount of BST-2 in the cell, requiring more Vpu to counteract it. This left less Vpu available to stop NK cells, allowing them to hunt and kill virally infected cells.

Dr. Hultquist and colleagues used an innovative combination approach to investigate how the viral protein Vif hijacks the machinery a cell uses to degrade unwanted proteins, causing it instead to destroy APOBEC3—an important antiviral host cell protein. The researchers noted that better understanding these virus and host interactions could offer new targets for antiviral therapies and vaccines.

Impact

These studies each show that viral and host immune system interactions can be manipulated to develop more effective treatments.

amfAR’s Role

Both Drs. Jonathan Richard and Judd Hultquist are funded by amfAR.

Original Articles

https://www.ncbi.nlm.nih.gov/pubmed/31253590

https://www.ncbi.nlm.nih.gov/pubmed/31213558

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

Mapping an HIV Vaccine Target

Researchers gain new insights into the potential power of broadly neutralizing antibodies 

Background 

Dr. Marit Van Gils

There is currently no HIV vaccine capable of eliciting protective immunity. One promising area of vaccine research has focused on broadly neutralizing antibodies (bNAbs)—specialized antibodies capable of inactivating diverse types of HIV. Of interest to researchers are a small number of people living with HIV called “elite neutralizers” who naturally develop bNAbs, providing models for vaccine development. 

bNAbs obtained from such elite neutralizers are being studied for their possible use in HIV prevention, treatment, and cure interventions. While they have shown much potential—inactivating about half of all variants of HIV—there remain obstacles such as how to extend the duration of protection and how these antibodies can more effectively inactivate the virus.  

The Research Question 

Last year, researchers were able to protect monkeys against SIV—an HIV-like virus that causes disease similar to AIDS—through the infusion of bNAbs sourced from elite neutralizers. The study found that genetically modified bNAbs could provide long-term protection against the virus, and the modification did not affect the way they bound to the virus.  

Previous studies have demonstrated which region of the virus is vulnerable to bNAbs. In this study, amfAR-funded researchers asked: How do changes in the way binding at this region occurs aid recognition and neutralization of HIV? 

Findings 

Dr. Gabriel Ozorowski

Researchers studied the region of HIV recognized by a bNAb obtained from an elite neutralizer. They used highly sophisticated scanning procedures such as ultra-high resolution cryo-electron microscopy—which examines the topography of proteins—to capture the molecular interactions between the antibody and the participant’s own HIV. Scientists used these stop motion animation-like scanning procedures to locate points of contact between the antibody and the virus, and to piece together specific interactions that lead to the antibody’s potent ability to neutralize HIV. 

Researchers focused on interactions at the fusion peptide—a viral protein that folds back on itself to pull the bulk of the virus inside the cell. The fusion peptide is surrounded by a shield of sugar molecules that makes it largely inaccessible. Yet some antibodies have been known to penetrate the shield and neutralize the fusion peptide. The scanning techniques used by the researchers here revealed that this elite neutralizer’s bNAb could interact with the fusion peptide in an entirely new way. They also found that the fusion peptide is much more flexible than previously thought, making it amenable to targeting by this and perhaps other antibodies.   

Impact 

Knowledge of how the HIV fusion peptide can twist into multiple conformations, or shapes, illuminates antibody recognition strategies that can be used for HIV vaccine design.

amfAR’s Role 

Both Drs. Ozorowski and van Gils are funded by amfAR through the Mathilde Krim Fellowship program.

Original Article 

http://www.ncbi.nlm.nih.gov/pubmed/31194940

Dr. Laurence is amfAR’s senior scientific consultant.

Combination Treatment Cures Mice of HIV

Antiretroviral therapy (ART) has been extremely effective at reducing HIV in the blood to below levels of detection, but less able to stop viral activity in the tissues. Efforts to achieve a cure for HIV would therefore be aided by stopping this source of virus that continually feeds the HIV reservoir.

Dr. Howard Gendelman of the University of Nebraska Medical Center has developed LASER ART, a slow-release, long-acting nanomedicine version of ART that penetrates deep into tissues to effectively extinguish this source of viral activity. This powerful new technology raises the question: With a newly contained viral reservoir, could the right intervention have a chance to cure HIV?

In a July article in Nature Communications, Dr. Gendelman and Dr. Kamel Khalili, of the School of Medicine at Temple University, demonstrate that it may be possible.

Using humanized mice infected with HIV and treated with LASER ART, Dr. Khalili administered CRISPR, a protein that acts like a molecular scissor, to cut out HIV DNA from infected cells. Sequential treatment with LASER ART followed by CRISPR eliminated viral rebound in two of six mice when ART was stopped—a key measure to determine whether a cure has been achieved.

The research team went a step further, however, transferring cells from these two potentially cured mice into different, uninfected mice and confirming that no HIV infection was transmitted.

These encouraging results are a boon to the field of gene therapy, which is increasingly turning to various types of molecular scissors, including CRISPR, Brec1, and others to eliminate HIV from the body. amfAR’s is currently funding several such innovative gene therapy approaches through its ARCHE-GT collaborative grant initiative.

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

amfAR Advances Collaborative Bioengineering Studies Aimed at Curing HIV

New amfAR grants support third phase of high-tech projects
using nanotechnology and protein “fingerprinting”

Media Contact:

Mary Pavlu, amfAR
P: 212.806.1602
E: mary.pavlu@amfar.org

NEW YORK, April 12, 2019 – amfAR, The Foundation for AIDS Research, has awarded new funding to researchers using cutting-edge technology to address the main barrier to a cure for HIV: the persistent reservoirs of virus not cleared by antiretroviral therapy. Totaling $1.6 million, this new round of Investment grants launches the critical third phase of two research projects launched in 2017.

Investment awards are milestone-based grants for research studies undertaken over four years in three phases. In this third phase, bioengineers are working in partnership with leading HIV cure scientists to tackle some of the most difficult challenges in HIV cure research. The grants are part of amfAR’s $100 million Countdown to a Cure for AIDS initiative, which is aimed at developing the scientific basis of a cure by the end of 2020.

“At amfAR, we believe that combining innovation with collaboration is the surest way to a cure for HIV,” said amfAR CEO Kevin Robert Frost. “These awards are an outstanding example of that philosophy in action and we will follow the progress of these exceptional grantees with great interest.” 

One of the biggest challenges in HIV cure research is that until now, it has been impossible to pinpoint and kill HIV reservoir cells, since no one has been able to identify a unique characteristic, or marker, that sets them apart from non-reservoir cells. Dr. Hui Zhang of Johns Hopkins University, a leading expert in the field of mass spectrometry, is applying this protein “fingerprinting” technique to the challenge.

In the first two phases of the study, Dr. Zhang used mass spectrometry to scan the surface of human cells for proteins that discriminate between latently infected and uninfected cells. After scanning a variety of cell lines, she identified 17 potential targets. In phase three, Dr. Zhang is teaming up with HIV scientist Dr. Weiming Yang, also of Johns Hopkins University, to determine in a preclinical study whether specifically killing cells displaying any of these 17 proteins will eliminate the latent reservoir.

On the West Coast, Dr. Keith Jerome and bioengineer Dr. Kim Woodrow, both at the University of Washington in Seattle, are focusing on identifying a potent latency reversing agent (LRA) that can shock the reservoir out of latency, the first stage in a “shock and kill” strategy to cure HIV.  

One of the most effective classes of LRAs developed to date, ingenols, has significant toxic side effects and can lead to expansion of the viral reservoir. To reduce this toxicity and prevent expansion of the reservoir, Drs. Woodrow and Jerome are using nanoparticles—highly versatile vehicles that, like a Trojan horse, can deliver multiple drugs to a single cell. To date, the researchers have formulated nanoparticles loaded with LRAs including an ingenol and have succeeded in greatly reducing toxicity in a mouse model. In the next phase, they will test their nanoparticles for elimination of the reservoir in a preclinical study.

“These four-year investment grants have enabled us to support some remarkable collaborative research that needs more than just a year or two to show meaningful results,” said Dr. Rowena Johnston, amfAR vice president and director of research. “If these researchers manage to accomplish what they’ve set out to do, we will have overcome two of the biggest obstacles standing in the way of 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 advocacy.  Since 1985, amfAR has invested nearly $550 million in its programs and has awarded more than 3,300 grants to research teams worldwide.

Could Gene Therapy Cure HIV?

Upcoming Advances in HIV Gene Therapy

In August, scientists will discuss their latest findings at the 5th Conference on Cell & Gene Therapy for HIV Cure in Seattle. amfAR’s research will feature prominently, including an update from ICISTEM, the amfAR-initiated and funded European consortium that reported a few months ago on the London patient. Several members of amfAR’s ARCHE-GT consortium will also report on their combination approach to cutting HIV DNA out of infected cells and boosting T cell and antibody responses against any remaining virus.

Background

Rowena Johnston, Ph.D.

The promise of gene therapy is beginning to make its way into the clinic. In 2017, the FDA approved two CAR T cell therapies for cancers of the immune system, and another gene therapy to correct a gene mutation that causes retinal dystrophy. And in May 2019, Zolgensma was approved as a one-time treatment for children under two years of age with spinal muscular atrophy.

The number of FDA-approved gene therapies appears set to grow in the coming years, with nearly 4,000 clinical trials underway to address illnesses ranging from rare inherited conditions to those that rank among the most common killers, including cancer, heart disease, Alzheimer’s disease, and diabetes.

The Research Opportunities

In some respects, HIV is a conceptually simple target because it exists as a strand of DNA—much like a gene—inserted into the normal DNA of human immune cells. Indeed, many research groups are exploring a range of tools that could cut this strand of HIV DNA out of infected cells and thus remove the virus from the body.

However, HIV is a complex virus that provides numerous other avenues of attack. For example, some research groups are exploring whether cutting out the gene for CCR5, and thus removing the CCR5 protein—the main doorway through which HIV enters cells—might cure HIV along similar lines to the Berlin patient’s cure. The HIV remission observed in the London and Düsseldorf patients—members of amfAR’s ICISTEM cohort—lends additional optimism to this approach.

The possibilities don’t end there. Protective genes could be inserted; new or improved immune function could be engineered; individual or multiple HIV genes could be turned off; and any or all of these approaches could be combined with other gene or traditional therapies.

Anticipated Conference Highlights

The conference will begin with a session on stem cell transplantation and gene editing, featuring a plenary talk delivered by ICISTEM researchers. Subsequent sessions will feature updates on CAR T cells and other T cell therapies, as well as lessons from cell and gene therapy in other diseases.

Day two of the conference will focus on in vivo delivery of gene therapy. Researchers from amfAR’s ARCHE-GT consortium will present their progress on using different methods to deliver gene-editing tools, for example via intravenous injection.

Impact

Although gene therapy approaches have shown much promise in various diseases including HIV, they are currently very expensive. Thus far, approved gene therapies cost up to $2 million, partly due to the complexity of preparing the gene therapy product. In vivo delivery could make gene therapy substantially less expensive and more easily deliverable to people around the world living with HIV.

amfAR’s Role

amfAR is currently supporting multiple gene therapy approaches to curing HIV and is providing support to the 2019 Conference on Cell & Gene Therapy for HIV Cure.

Conference Information

Researchers looking for more information about the conference, including registration and late-breaker abstract submission, should visit https://www.cgt4hivcure2019.org/

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

A Biomarker for the “Active” HIV Reservoir?

Background 

HIV persists in a small number of infected cells—the viral reservoir—that are not cleared from the body by antiretroviral therapy. A major goal of HIV cure research is to identify a molecule, or biomarker, that distinguishes these reservoir cells from healthy cells. Having such a biomarker would allow researchers to target these reservoir cells and clear them with precision.  

Co-leader of the study, Dr. Peter Hunt

The Research Question 

In 2017, a team of researchers in France reported that they had found a potential biomarker of the reservoir in the blood—a protein called CD32. In their attempts to replicate the discovery, several other research teams found that CD32 may be a marker of HIV activity in blood cells rather than a specific marker of the latent reservoir. Scientists in this study ask: Could CD32 be a biomarker of HIV activity in the tissues, too? 

Findings 

Scientists examined gut biopsies from four study participants whose medication had reduced the HIV in their blood to undetectable levels. First, researchers noted that despite having undetectable virus in the blood, about four in every 100,000 cells in the tissue had jump-started activity of the provirus, meaning they had begun the first steps towards producing new viruses. These “actively” infected cells may be the first to re-seed viral infection in the blood if antiretroviral therapy is stopped. 

Next, the researchers explored whether CD32—the possible biomarker—was present in the actively infected cells, and to what degree. Using two separate techniques, the researchers found that those with undetectable virus in the blood had 100 times fewer actively infected cells in the tissue than those with detectable virus in the blood (viremia). But by one assay, between 60 and 100 percent of actively infected cells had CD32, compared to only 20 percent in those with viremia.  

Co-leader of this study, Dr. Timothy Henrich

Impact 

This study confirms the conclusion of other researchers that CD32 may not be a biomarker of the latent reservoir. However, CD32 may be a biomarker of what might be called the active reservoir—the persistent virus that is probably first to re-seed infection when antiretroviral therapy is stopped. Thinking on the nature of the reservoir is evolving to include not only latent, but also active reservoir, and both are major barriers to a cure. Finding a way to differentiate cells harboring active reservoir from healthy, uninfected cells would be an important advance. 

amfAR’s Role 

The co-lead scientists of this study, Drs. Timothy Henrich and Peter Hunt, are funded by amfAR and are members of the amfAR Institute for HIV Cure Research. 

Original Article 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508427/

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

amfAR: The Road to a Cure

amfAR: The Road to a Cure