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.

How HIV Establishes Its Reservoirs

The vast majority of these updates have described methods for eliminating the primary barrier to a cure: the latent reservoir of HIV that persists in infected individuals despite receiving antiretroviral therapy. Now an international team of researchers reports a major new finding on how this reservoir is actually formed, and what it implies for cure strategies.

Dr. Liang Shan

Dr. Liang Shan

The research was reported in the October issue of the journal Immunity by Dr. Liang Shan, an amfAR Mathilde Krim Fellow working in the laboratory of Dr. Robert Siliciano at Johns Hopkins University in Baltimore, along with colleagues from Yale University in New Haven, CT, Sun Yat-sen and Guangzhou Medical Universities in China, National Taiwan University Hospital in Taipei, North Carolina State University in Raleigh, and Washington University in St. Louis.

Shan and colleagues note that in untreated patients, HIV replicates continuously, avoiding immune responses through rapid evolution in a process known as viral escape. But then why should HIV bother to establish reservoirs, given this ability to evolve and evade? Based on their data, the researchers argue that latency is simply an “unfortunate consequence” of CD4+ T cell infection within a narrow time frame after T cells are activated.

They report that during the natural process of T cell transition from one functional state to another—referred to as EMT, or effector-to-memory transition—T cells temporarily increase the expression of CCR5, a critical receptor for HIV, and decrease the function of certain normal cell genes necessary for HIV growth. So the virus gets into the cells more easily via the abundant CCR5, but then is rendered dormant because of dampened gene activity.

Shan and associates didn’t stop there. They found that this process of viral latency could be interrupted by HIV-specific CD8+ killer T cells and concluded that their finding has “implications for elimination of latent HIV-1 infection by T cell-based vaccines.”

Dr. Laurence is amfAR’s senior scientific consultant.

Scientists Identify HIV’s ‘Hiding Place’

Scientists from the Westmead Institute for Medical Research in Australia have identified the specific immune cells in the body that harbor most of the HIV reservoir, the main barrier to a cure.

Dr. Sarah Palmer

Dr. Sarah Palmer

The study, which was partially funded by amfAR and published in the October 17 issue of Cell Reports, found that genetically intact and presumably replication-competent HIV hides in effector memory T cells, where it avoids detection by the immune system. These are the same white blood cells that “remember” previous infections and provide lifelong immunity to diseases such as chickenpox or measles. Replication-competent HIV DNA produces infectious particles.

“HIV is really very clever,” said amfAR-funded scientist Dr. Sarah Palmer, an associate professor at the University of Sydney and deputy director of the Centre for Virus Research at the Westmead Institute. “Essentially it is hiding in the exact same cells within the immune system that are meant to attack it.”

Palmer and her colleagues developed a next-generation genetic sequencing assay known as FLIPS (Full-Length Individual Proviral Sequencing) to determine where and how much replication-competent virus remained in six HIV-infected individuals on long-term antiretroviral therapy (ART). The assay measures intact HIV proviruses to deduce the amount of replication-competent virus in the body. Using the efficient, high-throughput technology, they discovered that about 70% of presumably replication-competent virus hides in specific subsets of CD4+ T cells.

Interestingly,  the researchers found that only 5% of all HIV DNA present in these participants was genetically intact. (The other 95% was defective, i.e., noninfectious.) However, this small proportion hides in the effector memory T cells and is the likely source of viral rebound after ART cessation.

“This virus inserts its genome into the body's memory cells and sits there quietly avoiding detection by the immune system,” Palmer said. "These infected cells go into a resting state and stop producing HIV, but these latent cells can wake up and start making infectious HIV.”

Palmer said if a person stops taking ART, the virus that is hidden in effector memory T cells can return and start producing more HIV. The virus will spread throughout the body within weeks of stopping ART, she said.

She concluded: “Now that we’ve identified where the replication-competent virus is hiding, we can start work towards targeting these cells with new therapies aimed at fully eliminating HIV from the body.”

See also: Scientists find where HIV 'hides' to evade detection by the immune system

To Reverse HIV Latency, Two Drugs Are Better Than One

Dr. Robert Siliciano

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.

Combination Antibody Strategy Shows Promise for HIV Cure

A combination of broadly neutralizing antibodies protected monkeys from infection with an HIV-like virus better than single antibodies in two recent, separate studies.

The results offer further evidence that a combination strategy may be the key to preventing HIV infection. Previous studies have found that individual antibodies do not provide sufficient protection from the virus.

Dr. Rowena Johnston

Dr. Rowena Johnston

“The virus is just so good at mutating away from any single thing we throw at it,” said amfAR Vice President and Director of Research Dr. Rowena Johnston in an interview with HealthDay. “When we treat HIV, you can’t give a single antiretroviral drug. You have to give a combination of at least two and optimally three. They are now also looking at this idea for antibodies.”

In one study, an amfAR-funded research team injected monkeys with a cocktail of two HIV-blocking antibodies and then exposed them to two different strains of SHIV (a combination of HIV and SIV—the simian version of HIV). Each strain was vulnerable to one of the antibodies.

The monkeys that received one of the antibodies individually became infected with the strain that was not sensitive to the one antibody; however, when they received the two-antibody cocktail, they were protected against both.

In the other study, scientists from the National Institutes of Health (NIH) and the Paris-based pharmaceutical company Sanofi created a three-pronged antibody based on three individual antibodies, each of which neutralizes many strains of the virus. The “trispecific” antibody binds to three different vulnerable sites on the virus.

None of the monkeys given the three-pronged antibody became infected after being exposed to two strains of SHIV.

Plans are underway to begin clinical trials of both the trispecific antibody and the two-antibody cocktail in the hope of eventually using the strategies for both HIV prevention and treatment.

However, as Johnston noted to HealthDay, all antibodies die off quickly. That means, “if you were going to use these in clinical practice to prevent HIV infection, you would have to repeatedly administer them,” perhaps as often as every several weeks, she said.

Both studies were published September 20 in the journals Science and Science Translational Medicine.

Read a press release on the NIH study here.

Using Groundbreaking CAR-T Cancer Therapy to Eliminate HIV

On August 30, 2017, the U.S. Food and Drug Administration approved Kymriah as the first gene therapy for patients with a drug-resistant form of acute leukemia. The chimeric antigen receptor (CAR) therapy involves modifying a patient’s own T cells to seek and destroy cancer cells. It is a one-time treatment, and for many people, a lifesaving one. The approval of this therapy received worldwide publicity. But what may come as a surprise to many is the critical role HIV research played in the development of Kymriah, and how this proof-of-concept treatment for cancer relates to progress toward an HIV cure.

Dr. Scott Kitchen

Dr. Scott Kitchen

Writing in the September issue of the journal Translational Research, amfAR-funded scientist Dr. Scott Kitchen and colleagues from the University of California, Los Angeles note that most investigators believe that enhancing a person’s natural immune response will be key in eliminating HIV-infected cells. Indeed, HIV-specific CD8+ killer T cells can be engineered to inhibit HIV growth and reduce the size of the HIV reservoir in the test tube. But this strategy has numerous drawbacks, including the need to alter HIV killer cells based on an individual’s HLA tissue type. CARs are based on engineering CD4+ T cells, which don’t have that requirement. Almost all HIV-infected patients can be treated with the therapy, regardless of genetic makeup.

The researchers explain that the first CAR T cells to be used in clinical trials were actually designed and tested for the treatment of HIV—not cancer. In addition, in order to enable those cells to recognize infected cells, a self-inactivating lentivirus—a modified form of HIV—was used to introduce the necessary genes. However, pilot trials showed less than satisfactory results, as unlike cancer, HIV can attack the very CAR T cells administered to fight the infection. With this in mind, Kitchen and associates discuss several novel approaches to enhance the activity of anti-HIV CAR T cells and to protect them against infection.

These strategies include removing, through genetic engineering, the primary HIV co-receptor CCR5. (The “Berlin patient” became the first person to be cured of HIV after receiving a stem cell transplant from a donor with a CCR5 mutation.) The scientists also propose a combination approach to kill infected cells and eliminate latent HIV reservoirs.

The authors conclude: “CAR-based therapy for HIV infection is becoming a promising approach to provide lifelong immune surveillance and viral suppression without the use of antiretroviral therapy … a closer step toward a functional cure for HIV.”

Dr. Laurence is amfAR’s senior scientific consultant. 

Injection of Specific Antibodies May Reduce HIV Viral Load

While the role of antibodies in preventing infection is clear, a growing number of researchers are enlisting antibodies to help cure HIV. One of the most promising avenues to achieve this is passive immunization, in which antibodies are injected directly into the patient.

Dr. Dan Barouch

Dr. Dan Barouch

In the August issue of the Journal of Virology, amfAR-funded scientist Dr. Dan Barouch of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, 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, uses a passive immunization approach to explore the potential role of antibodies in curing HIV infection.

Barouch and associates tested two antibodies, PGT121 and N6, in 18 monkeys infected with SHIV, a combination of HIV and SIV (the simian form of the virus). Both PGT121 and N6 are known to be active against HIV. The monkeys were treated with either PGT121 or 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. The authors note that the monkeys’ naturally occurring antibodies and immune responses to SHIV were not enhanced as a result of the PGT121 or N6 infusions, arguing against their contribution to the observed viral effects.

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.

Understanding Exactly How the ‘Berlin Patient’ Was Cured

Understanding Exactly How the ‘Berlin Patient’ Was Cured

The strongest proof that HIV can be cured comes from the case of Timothy Brown, the “Berlin patient.” That triumph was predicated on physicians taking advantage of nature’s own experiment: the existence of a genetic mutation in a normal cell protein, CCR5, the main co-receptor that HIV uses to gain entry into a cell.

A Gene Therapy Revolution?

New amfAR gene therapy grants awarded as FDA panel recommends approval of first ever gene therapy-based treatment in the U.S.

On July 12, a Food and Drug Administration panel for the first time recommended approval in the U.S. of a gene therapy-based treatment. The treatment, first developed by Dr. Carl June of the University of Pennsylvania, a member of amfAR’s Cure Council, is based on the use of so-called CAR cells to kill cancer cells.  

On July 13, amfAR announced two new grants to research teams pursuing similar strategies involving CAR (chimeric antigen receptor) cells, which have shown significant potential for their ability to kill HIV-infected cells. The grants are part of a new round of seven awards totaling $2.3 million in support of gene therapy-based approaches to curing HIV.  They were awarded through the amfAR Research Consortium on HIV Eradication (ARCHE), a program that fosters collaboration among teams of scientists. 

Curing HIV is no longer a pipe dream, and the case of ‘the Berlin patient’ provides proof-of-principle that a cure is possible. However, several complex scientific challenges remain, and these new grants reflect amfAR’s determination to pursue a range of strategies to overcome them.

CAR Cells and Cure

Scott Kitchen, Ph.D., of University of California, Los Angeles, plans to improve the effectiveness of CAR cells at killing HIV-infected cells by increasing their ability to detect the appropriate target cells and prolonging their survival. He also plans to engineer improvements to minimize the loss of CAR cells to attack by the immune system, and to design a mechanism to “switch off” CAR cells should they become unsafe or are no longer needed.

And a team led by Richard Wyatt, Ph.D., of The Scripps Research Institute in La Jolla, CA, plans to generate CAR T cells with the ability to kill HIV-infected cells just as they begin to produce virus. Additionally, the CAR T cells will be engineered to produce antibodies that may destroy virus and the cells that produce it.

The other grantees are: Hildegard Büning, Ph.D., of Hannover Medical School in Hannover, Germany; Keith Jerome, M.D., Ph.D., of University of Washington in Seattle; Hans-Peter Kiem, M.D., F.A.C.P., of Fred Hutchinson Cancer Research Center, Seattle; Yasuhiro Takeuchi, Ph.D., of University College London, United Kingdom; Drew Weismann, M.D., Ph.D., of University of Pennsylvania, Philadelphia.

Genetic Scissors 

The researchers will pursue projects aimed at: designing and refining vectors that can accurately target the cells that make up the reservoir and regions such as the lymph nodes, where the reservoir cells tend to be concentrated; and exploring the potential of using viral and non-viral delivery mechanisms to deliver emerging types of genetic scissors that could cut the virus out of human DNA.

“Curing HIV is no longer a pipe dream, and the case of ‘the Berlin patient’ provides proof-of-principle that a cure is possible,” said amfAR Chief Executive Officer Kevin Robert Frost, referring to the only person known to have been cured of HIV. “However, several complex scientific challenges remain, and these new grants reflect amfAR’s determination to pursue a range of strategies to overcome them.” 

New Innovation Grants

In a second round of grants, amfAR awarded $1.2 million to six researchers who will explore mechanisms of HIV persistence and the potential for HIV eradication. These “Innovation” grants are designed to test and advance innovative ideas in the early stages of testing.

Through these projects, we will continue to forge the scientific alliances − within HIV and beyond − that we believe are our best hope for accelerating progress toward a cure.

For instance, Andrew Badley, M.D., from the Mayo Clinic College of Medicine in Rochester, MN, will test whether ixazomib, a drug currently used to treat the blood cancer multiple myeloma, can reduce the size of the viral reservoir in the body. Joshua Schiffer, M.D., from Fred Hutchinson Cancer Research Center in Seattle, WA, will test a drug normally used to prevent organ transplant rejection for its potential to eliminate the persistent HIV reservoir.

Andrew Henderson, M.D., from Boston University School of Medicine in Boston, MA, and Fabio Romerio, Ph.D., from University of Maryland, Baltimore, MD, will both explore a cure strategy known as “block & lock,” which aims to permanently silence HIV and prevent the emergence of virus when antiretroviral therapy is stopped.

Brad Jones, Ph.D., from The George Washington University, Washington, DC, aims to develop a new class of broadly neutralizing antibodies that enable the immune system to recognize proteins not normally accessible to the body’s antibody making machinery. The goal is to increase the number of people in whom broadly neutralizing antibodies are able to find and kill HIV-infected cells.

Berlin Patient

And to better understand how Timothy Brown, “the Berlin patient,” was cured of HIV, Benjamin Burwitz, Ph.D., from Oregon Health and Science University in Portland, will explore the precise mechanisms that led to his cure by generating a monkey model lacking the protein CCR5, the primary means by which most types of HIV infect cells.

“These two rounds of grants get to the heart of the scientific challenges we face in our search for a cure,” said Dr. Rowena Johnston, amfAR’s vice president of research. “Through these projects, we will continue to forge the scientific alliances − within HIV and beyond − that we believe are our best hope for accelerating progress toward a cure.” 

Learn more about the ARCHE and Innovation grants.

New amfAR Research Grants Advance Gene Therapy and Other Innovative Approaches to HIV Cure

More than $3.5 million awarded to researchers
aiming to overcome barriers to curing HIV
 

 

NEW YORK, NY, July 13, 2017 – amfAR, The Foundation for AIDS Research, has awarded more than $3.5 million for 13 new research grants to support innovative approaches to depleting or eliminating the persistent reservoirs of HIV not cleared by antiretroviral therapy – considered the main barrier to a cure. The grants represent the latest investments in the Foundation’s Countdown to a Cure for AIDS initiative, which is aimed at developing the scientific basis of a cure by the end of 2020. To date, amfAR has awarded Countdown grants totaling close to $42 million to support research conducted by more than 222 scientists working at 74 institutions in 10 countries around the world.

“Curing HIV is no longer a pipe dream, and the case of ‘the Berlin patient’ provides proof-of-principle that a cure is possible,” said amfAR Chief Executive Officer Kevin Robert Frost, referring to the only person known to have been cured of HIV. “However, several complex scientific challenges remain, and these new grants reflect amfAR’s determination to pursue a range of strategies to overcome them.”  

Through the amfAR Research Consortium on HIV Eradication (ARCHE), a program that fosters collaboration among teams of scientists, more than $2.3 million in grants was awarded to seven teams of researchers working on gene therapy-based approaches to curing HIV. While pharmacological and immunological approaches remain the dominant cure strategies, the Berlin patient’s cure involved a procedure that points to the promise of gene therapy.

The grantees are: Hildegard Büning, Ph.D., of Hannover Medical School in Hannover, Germany; Keith Jerome, M.D., Ph.D., of University of Washington in Seattle; Hans-Peter Kiem, M.D., F.A.C.P., of Fred Hutchinson Cancer Research Center, Seattle; Scott Kitchen, Ph.D., of University of California, Los Angeles; Yasuhiro Takeuchi, Ph.D., of University College London, United Kingdom; Drew Weissman, M.D., Ph.D., of University of Pennsylvania, Philadelphia; and Richard Wyatt, Ph.D., of The Scripps Research Institute in La Jolla, CA.

Gene therapy offers the tantalizing possibility of manipulating DNA as a means of attacking infected cells that make up the HIV reservoir, altering the susceptibility of cells to HIV infection, or enhancing the ability of the immune system to attack or block the virus. 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.

The researchers will pursue projects aimed at: designing and refining vectors that can accurately target the cells that make up the reservoir and regions such as the lymph nodes, where the reservoir cells tend to be concentrated; using so-called CAR T cells, which have shown remarkable promise in clearing some types of cancer, as a potential means of killing HIV-infected cells; and exploring the potential of using viral and non-viral delivery mechanisms to deliver emerging types of genetic scissors that could cut the virus out of human DNA.

In a second round of grants, amfAR awarded $1.2 million to six researchers who will explore mechanisms of HIV persistence and the potential for HIV eradication. These “Innovation” grants are designed to test and advance innovative ideas in the early stages of testing.

For instance, Andrew Badley, M.D., from the Mayo Clinic College of Medicine in Rochester, MN, will test whether ixazomib, a drug currently used to treat the blood cancer multiple myeloma, can reduce the size of the viral reservoir in the body. Joshua Schiffer, M.D., from Fred Hutchinson Cancer Research Center in Seattle, WA, will test a drug normally used to prevent organ transplant rejection for its potential to eliminate the persistent HIV reservoir.

Andrew Henderson, M.D., from Boston University School of Medicine in Boston, MA, and Fabio Romerio, Ph.D., from University of Maryland, Baltimore, MD, will both explore a cure strategy known as “block & lock,” which aims to permanently silence HIV and prevent the emergence of virus when antiretroviral therapy is stopped.

Brad Jones, Ph.D., from The George Washington University, Washington, DC, aims to develop a new class of broadly neutralizing antibodies that enable the immune system to recognize proteins not normally accessible to the body’s antibody making machinery. The goal is to increase the number of people in whom broadly neutralizing antibodies are able to find and kill HIV-infected cells.

And to better understand how Timothy Brown, “the Berlin patient,” was cured of HIV, Benjamin Burwitz, Ph.D., from Oregon Health and Science University in Portland, will explore the precise mechanisms that led to his cure by generating a monkey model lacking the protein CCR5, the primary means by which most types of HIV infect cells.

“These two rounds of grants get to the heart of the scientific challenges we face in our search for a cure,” said Dr. Rowena Johnston, amfAR’s vice president of research. “Through these projects, we will continue to forge the scientific alliances - within HIV and beyond - that we believe are our best hope for accelerating progress toward a cure.”

Click here for full descriptions of the ARCHE and Innovation grants.

 

About amfAR:

hiv-virus-14152815.jpg

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 more than $480 million in its programs and has awarded grants to more than 3,300 research teams worldwide.

# # #

ARCHE Gene Therapy Grants

July 2017

Hildegard Büning, Ph.D. – principal investigator
Hannover Medical School, Hannover, Germany
$386,578 (109570)
Vector-mediated in vivo targeting of HIV reservoir cells or provirus elimination: To maximize safety of gene therapy, methods to specifically target reservoir cells are required. The HIV reservoir consists mainly of CD4+ T cells, with certain subsets more commonly harboring latent HIV. Dr. Büning plans to design an adeno-associated viral vector that specifically targets one of these main subsets, the central memory T cells. The vector will be designed to carry a gene editing tool called Brec1, previously shown to suppress HIV. One reported advantage of Brec1 over other gene editing tools is the apparent lack of off-target effects. 

Keith Jerome, M.D., Ph.D. – principal investigator
University of Washington, Seattle, WA
$399,955 (109575)
Subcutaneous administration of DARPin-modified adeno-associated virus vectors for selective targeting of CD4+ T cells: Curing a diffuse disease such as HIV, as opposed to a localized tissue-specific disease, requires a way to target the gene therapy to the target cells of interest, which in HIV are dispersed throughout the body. Dr. Jerome plans to use adeno-associated viral virus vectors engineered to utilize small, antibody-like  proteins to target the vectors and their gene-editing cargo directly to CD4+ T cells, which comprise the majority of the HIV reservoir. He will also experiment with ways of infusing the vectors such that they preferentially reach the lymph nodes, where most reservoir cells are found.

Hans-Peter Kiem, M.D., F.A.C.P. – principal investigator
Fred Hutchinson Cancer Research Center, Seattle, WA
$200,000 (109608)
Engineering blood cells to produce broadly neutralizing anti-HIV antibodies: Antibodies have been the focus of increasing optimism in the HIV cure research field due to their ability to not only neutralize virus particles, but also to target and help kill infected cells. Dr. Kiem plans to genetically modify immune system progenitor cells to serve as a constant source of antibodies. By engineering cells that will differentiate into a variety of types of immune cells, Dr. Kiem hopes that the progeny cells will migrate to various parts of the body, including lymph nodes and brain known to be important reservoirs of HIV.

Scott Kitchen, Ph.D. – principal investigator
University of California, Los Angeles, Los Angeles, CA
$400,000 (109577)
Optimized efficacy and persistence of engineered HIV-specific cellular immunity: Chimeric antigen receptor (CAR) cells have shown remarkable promise in their ability to clear some cancers in patients, and additionally have shown potential in HIV cure. Dr. Kitchen plans to improve the ability of CAR cells to kill HIV-infected cells by increasing their ability to detect the appropriate target cells and prolonging their survival. He also plans to engineer improvements to minimize the loss of CAR cells to attack by the immune system, and to design a mechanism to “switch off” CAR cells should they become unsafe or are no longer needed.

Yasuhiro Takeuchi, Ph.D. – principal investigator
University College London, London, United Kingdom
$360,034 (109584)
LentiStim: Mass production of lentiviral vectors for in vivo gene delivery: Curing HIV by gene therapy may require long-term persistence of the gene editing tools delivered by lentiviral vectors, which are closely related to HIV. Because the reservoir that harbors persistent HIV consists almost entirely of resting cells, such vectors cannot gain entry into the cells to deliver their cargo. Dr. Takeuchi plans to modify lentiviral vectors with a cocktail of stimulatory molecules that induce an optimal level of activation in the target cell, thus allowing entry of the vector. The effectiveness of lentiviral vectors is also plagued by immune responses raised against the vector, so the team will produce vectors that are resistant to destruction by the immune system.

Drew Weissman, M.D., Ph.D. – principal investigator
University of Pennsylvania, Philadelphia, PA
$400,000 (109587)
Targeting of nucleic acid therapeutics to cure HIV: Gene therapy approaches to cure HIV include efforts to cut the virus out of the human DNA, or to imbue the human host cells with characteristics that protect them from infection. Dr. Weissman plans to employ nucleic acid therapeutics as the tools to edit DNA to achieve either or both of these goals. One advantage of nucleic acid therapeutics is the ability to administer them repeatedly without raising an immune response that would destroy them. He plans to optimize their delivery to the appropriate cells by packaging them inside lipid nanoparticles that can be engineered with surface particles that guide them to specific targets.

Richard Wyatt, Ph.D. – principal investigator
The Scripps Research Institute, La Jolla, CA
$199,362 (109618)
Vector-mediated in vivo targeting of HIV reservoir cells or provirus elimination: Chimeric antigen receptor (CAR) cells have shown remarkable promise in their ability to clear some cancers in patients, and additionally have shown potential in HIV cure. One advantage is their ability to overcome a cancer or virus-infected cell’s ability to hide from the immune system. Dr. Wyatt plans to generate CAR T cells with the ability to kill HIV infected cells just as they begin to produce virus. Additionally, the CAR T cells will be engineered to produce antibodies that can neutralize any virus that is produced.