What Can Frogs Contribute to Microbicide Development? amfAR September 2005 Grants
September 28, 2005—Do frogs hold a key to preventing HIV infection? Derya Unutmaz, M.D., a researcher in microbiology at Vanderbilt University, thinks they might and has been awarded a grant from amfAR to answer this question. Unutmaz’s study, “Amphibian-derived microbicides that inhibit HIV infection,” is one of 11 projects amfAR announced today aimed at improving understanding of HIV and AIDS, developing new therapies to treat and prevent infection, and perhaps, ultimately, finding a cure.
“These latest research grants show enormous promise,” said Dr. Rowena Johnston, amfAR’s director of research. “Dr. Unutmaz’s study is an excellent example of the kind of research amfAR supports – projects that seek out innovative ways to prevent infection and improve treatments for people living with HIV.”
A microbicide – a user-friendly product that, when applied topically, could block the transmission of HIV – is urgently needed to help stop the spread of AIDS. Such a product could empower women to protect themselves against HIV, while perhaps even allowing them to have children, an option that condoms do not offer.
Dr. Unutmaz has discovered that two small peptides derived from amphibians’ skin may serve as a basis for microbicides. With amfAR funding, his challenge will be determining how these peptides block HIV infection and its spread inside the body, to use this information to search for peptides that might be even more effective, and finally to ascertain how they could be used as microbicides.
Since its founding in 1985, amfAR has awarded more than $233 million in research grants. With a grantmaking philosophy that values novel approaches to the unanswered questions surrounding HIV, amfAR grantees and fellows are consistently at the forefront of AIDS research. Most recently, amfAR-funded research ultimately led to the latest new class of anti-HIV drugs, fusion inhibitors, introduced for use in 2003. Earlier this year, an amfAR-funded researcher provided the first structurally detailed images of gp120, one of HIV’s envelope proteins, before it binds to human cells, which may prove enormously valuable in the search for an AIDS vaccine.
In addition to advancing microbicide development, projects funded in this round of amfAR research awards include furthering understanding of the natural resistance factors that protect other species from HIV infection, and finding ways in which new therapies can be targeted to HIV that persists, despite the most effective drug treatment, in cellular and anatomical reservoirs in infected patients.
amfAR is the nation’s leading nonprofit organization dedicated to the support of AIDS research, AIDS prevention, treatment education and the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested more than $233 million in support for its programs and awarded grants to more than 2,000 research teams worldwide.
Nicolas Chomont, Ph.D.
Université de Montréal
Mentor: Rafick-Pierre Sekaly, Ph.D.
HIV reservoir in central memory T cells:
Reservoirs of HIV persist in patients even when HIV levels are so low that the virus cannot be detected by standard means. Dr. Chomont plans to identify characteristics of cells that HIV hides in so that they can one day be targeted by strategies designed to reduce or even eliminate residual HIV. He will also determine whether HIV exists in different forms (such as inside or outside the cell’s DNA) when it hides inside reservoir cells, so that treatment approaches that aim to flush out HIV can be tailored to particular forms of the virus.
Lei Fang, M.D., Ph.D.
The Salk Institute for Biological Studies
La Jolla, CA
Mentor: Nathaniel Landau, Ph.D.
Identification of novel host factors for HIV replication:
Over the past three years, several novel proteins that can prevent HIV infection have been identified within cells. Because they represent an opportunity for scientists to devise new strategies to fight HIV, Dr. Fang proposes to search for other such proteins by using two techniques, RNA interference and complementary DNA. These techniques have the potential to identify many new antiviral host factors that attack HIV at different points in its life cycle. New factors identified by Dr. Fang will yield information on the range of antiviral defenses and how they might be harnessed in clinical practice to fight the virus.
Patrick Harrington, Ph.D.
University of North Carolina at Chapel Hill
Chapel Hill, NC
Mentor: Ronald Swanstrom, Ph.D.
Characterization of HIV env variants that persist during HAART:
It is well known that current anti-HIV drug regimens (HAART) cannot eliminate HIV from an infected person. Less well understood is how and where a small fraction of HIV hides in the body to avoid being targeted by HAART. Dr. Harrington will measure differences in the ability of genetically distinct HIV viruses to survive during the first few days of HAART. He will then look to see whether HIV strains that survive longer tend to do so in certain cell types. Dr. Harrington’s research will extend our knowledge of where HIV hides to evade HAART, a step towards possibly using drugs to completely eliminate HIV.
Hendrik Huthoff, Ph.D.
London, United Kingdom
Mentor: Michael Malim, Ph.D.
The APOBEC3G-Vif interaction as a new HIV therapeutic target:
The human protein APOBEC3G can prevent HIV infection from spreading inside a person, but is normally prevented from doing so by the HIV protein Vif. Dr. Huthoff’s research will aid in the search for drugs that would reinstate APOBEC3G’s anti-HIV activity. He will identify the specific regions on both APOBEC3G and Vif responsible for mediating their interaction with one another, which will give a structural description that researchers could use to design drugs to inhibit this interaction. His research will also provide clues to how HIV, including Vif, evolves to outwit APOBEC3G.
Young Kyeung Kim, Ph.D.
Case Western Reserve University
Mentor: Jonathan Karn, Ph.D.
Kinetics of HIV reactivation in latently infected T cells:
If HIV hides in the host cell’s DNA in a latent state, existing anti-HIV drugs cannot destroy the virus. In order to flush the virus out so that it can be targeted by drugs, scientists need to understand the process whereby HIV can be activated. Dr. Kim will study a region of the virus that kickstarts its own activation, called the viral promoter, or LTR. She will assess which human and viral proteins pass signals to the LTR and in which sequence, in order to more fully understand how HIV could be activated as a therapeutic strategy to target otherwise latent virus.
Harmit Malik, Ph.D.
Fred Hutchinson Cancer Research Center
Evolutionary screen to identify novel TRIM restriction factors:
Viruses and the hosts they infect engage in an evolutionary tug-of-war: viruses evolve mechanisms to avoid destruction by the host, while hosts evolve ways to overcome these evasion strategies. Dr. Malik will study the TRIM family of proteins, one of which is already known to protect against HIV. He aims to identify other TRIM proteins that have undergone rapid evolution, since these are proteins likely to be involved in antiviral defenses. He will then test each of these TRIM proteins for the ability to protect against a range of viruses, including HIV. Finding new anti-HIV proteins will help scientists devise ways to strengthen our cellular antiviral defenses.
Deborah Palliser, Ph.D.
CBR Institute for Biomedical Research
Mentor: Judy Lieberman, M.D., Ph.D.
Harnessing RNA interference as an HIV microbicide:
RNA interference (RNAi) is a new gene therapy technology that could be used to reduce levels of, or even eradicate, genes that are needed for HIV infection. Dr. Palliser will build on previous research to optimize the use of RNAi in dendritic cells, which are believed to play an important role in the spread of the virus after sexual transmission. Issues she will work to resolve include: how to most efficiently deliver RNAi; whether there are unforeseen effects on cells; and how to cut gene levels without toxic effects. These studies will pave the way for future experiments in monkeys.
Virginie Sandrin, Ph.D.
University of Utah
Salt Lake City, UT
Mentor: Wesley Sundquist, Ph.D.
Mechanistic study of retroviral entry and restriction in vitro:
When HIV enters human cells, it must shed its coat so that the viral genetic material contained inside is free to insert itself into human DNA. One naturally occurring defense against HIV infection, TRIM5alpha, acts during this process to block the uncoating of HIV. Dr. Sandrin will use novel techniques to study how TRIM5alpha impedes this process and to identify human cell proteins that the virus co-opts to help free its genetic material. This information will help scientists develop new treatment strategies that could prevent HIV from inserting itself into human DNA and thus establishing lasting infection.
Chisu Song, Ph.D.
Vanderbilt University School of Medicine
Mentor: Christopher Aiken, Ph.D.
Mechanism of postentry restriction of HIV-1 by TRIM5alpha:
While scientists have recently learned that TRIM5alpha can inhibit HIV infection shortly after the virus enters a cell, the mechanism whereby the life cycle of the virus is interrupted is incompletely understood. Dr. Song plans to pursue his hypothesis that TRIM5alpha attaches to the core of the virus, or capsid, that contains the genetic material. He suggests that TRIM5alpha destabilizes the core and thereby interferes with the process of uncoating, during which the capsid peels away to reveal the virus’s genes, a critical step in the life cycle of HIV. A more thorough understanding of the process of uncoating and how TRIM5alpha might interfere with it could help scientists devise new anti-HIV therapeutics.
Derya Unutmaz, M.D.
Vanderbilt University Medical School
Amphibian derived microbicides that inhibit HIV infection:
Dr. Unutmaz has discovered two small proteins, collected from the skin of amphibians, that prevent HIV infection. Tests so far have indicated that these proteins may be ideal candidates to serve as microbicides, which are creams or gels applied to the vagina or rectum that could reduce the risk of sexual transmission of HIV. Dr. Unutmaz will continue to search for other amphibian skin-derived blockers of HIV infection. He will learn more about how these small proteins are able to destroy free-floating HIV as well as virus that has been absorbed into dendritic cells, which are believed to play an important role in spreading the virus after sexual transmission.
Susana Valente, Ph.D.
New York, NY
Mentor: Stephen Goff, Ph.D.
Human cellular factors that restrict HIV infection:
Dr. Valente and colleagues have identified two new cellular factors that, when present, appear to be capable of rendering cells up to one hundred times less susceptible to HIV infection. She plans to further characterize these newly identified factors, which appear to act at a different point in the HIV life cycle than any other restriction factors identified previously. She hopes to more fully understand the mechanism whereby these two factors inhibit HIV, which will in turn teach us more about the HIV life cycle and how it can be disrupted.