amfAR Announces July 2004 : Basic Research Grant and Fellowship Awards

July 6, 2004 - The American Foundation for AIDS Research (amfAR) announced today the award of more than $1 million in basic research grants and fellowships to further understand the HIV virus and devise improved methods to combat it. amfAR, which has supported basic research into HIV for almost two decades, has spent millions in advancing treatments for people infected with HIV and new methods of preventing infection in others. The grantees and fellows selected by amfAR’s Scientific Advisory Committee are a testament to the continued intellectual fervor that surrounds AIDS research as it enters its third decade.

“With the eyes of the scientific research community focused on the XV International AIDS Conference, these grants represent the vitality of basic biomedical research on HIV/AIDS,” said Dr. Rowena Johnston, who directs amfAR’s Basic Research program. Beginning next week in Bangkok, the International Conference provides scientists an opportunity to see the direction in which promising research is moving. “amfAR is funding studies in the vanguard of HIV research – the pioneering science that is likely to guide global research agendas on HIV for as long as we pursue improved treatments, a vaccine and a cure.”

This newest group of amfAR-funded scientists includes four fellows, working under the guidance of established AIDS researchers, seeking to understand how HIV initiates its own reproductive cycle; the process whereby the virus assembles its own parts into a complete whole; non-traditional methods for making a vaccine; and the transformations HIV undergoes to become a deadly virus late in HIV infection. Among the grantees is Dr. George Cohen, who aims to design a vaccine against the related monkey virus, SIV, using genetic engineering techniques in the monkeys’ own cells.

With the current round of funding, amfAR is also continuing its commitment to its Natural Host Resistance Factors initiative. Dr. Nathaniel Landau of the Salk Institute for Biological Studies in La Jolla, California, has received amfAR Basic Research support before. Following hard on the heels of his groundbreaking studies of the role played by APOBEC3G in HIV infection, Dr. Landau will now turn to the long-term goal of designing drugs that capitalize on its anti-HIV activity.

“Dr. Landau’s lab is a focal point in an emerging area of promise in the field of natural host resistance factors,” said Dr. Johnston. “APOBEC3G is the body’s natural HIV repellent. In the two years since the discovery of its role in HIV infection, it has become one of the most hotly pursued topics in AIDS research. APOBEC3G, along with other natural host resistance factors, has the potential to revolutionize how we treat, and maybe one day even eliminate, HIV.”

The American Foundation for AIDS Research is the leading U.S. 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 over $220 million in its programs and has awarded grants to more than 2,000 research teams worldwide.

GRANTS

Mary Barkley, Ph.D.
Case Western Reserve University
Cleveland, Ohio
$90,000

Novel hypothesis for HIV-1 RT resistance to NNRTIs: One of the major problems associated with anti-HIV therapy is the development of resistance, where drugs are no longer as effective at inhibiting the growth of HIV. Dr. Barkley proposes to study the mechanisms by which resistance develops to a major class of therapy, the non-nucleoside reverse transcriptase inhibitors (NNRTIs). She proposes to test her hypothesis that resistance to NNRTIs occurs when there are changes in the strength with which the two components of the enzyme reverse transcriptase associate with one another. Understanding how resistance arises will ultimately help scientists to develop more effective antiretroviral therapy.

Shan Cen, Ph.D.
SMDB Jewish General Hospital
Montreal, Canada
$84,984

The interaction between HIV-1 Gag and human APOBEC3G: If it becomes incorporated into newly made virus particles, APOBEC3G can prevent HIV from making infectious copies of itself. Dr. Cen will investigate the nature of the interactions between APOBEC3G and various components of the virus, including the viral protein Gag, which constitutes the major structural elements of HIV, as well as the role played by HIV's genetic material in influencing the APOBEC3G/Gag interaction. He will also determine how and in which cellular compartments infected cells make APOBEC3G. Answers to these questions may bring scientists closer to developing means to promote the incorporation of APOBEC3G into nascent virus particles.

George Cohen, Ph.D.
New England Primate Research Center
Southborough, MA
$90,000

Gene therapy for SIV-specific CD4 T cells: Dr. Cohen seeks to understand why the immune response elicited by HIV is insufficient to eliminate the virus. He will vaccinate monkeys against the related virus, SIV, extract immune cells from the monkey that are fighting the virus, genetically modify them, and infuse them back into the monkeys. The animals will then be reinfected with SIV to determine whether those cells maintain their ability to fight the virus or are more susceptible to viral infection than other immune cells, and whether the genetic modifications can protect those cells from being infected by SIV. Understanding these issues will ultimately help scientists develop an effective AIDS vaccine.

Ara Hovanessian, Ph.D.
UFR Biomedicale des Saints-Pères
Paris, France
$90,000

An efficient B-cell epitope vaccine candidate against HIV-1 infection: Dr. Hovanessian has identified a section of the HIV protein gp41 that is the same in all strains of the virus. He plans to capitalize on this finding by developing an AIDS vaccine that elicits antibodies to this short segment of gp41. Preliminary experiments in test tubes and small animals have demonstrated that his vaccine elicits antibodies that can disable the virus both by inhibiting entry of the virus into cells and disrupting the ability of newly produced virus to emerge from infected cells. Dr. Hovanessian now plans to fine-tune the details of the vaccine itself and to test its effectiveness in monkeys.

William James, Ph.D.
University of Oxford
Oxford, England
$47,514

Structural basis for pan-clade neutralization by aptamer B40: In a search for new ways to slow the ability of HIV to reproduce, Dr. James plans to investigate the use of aptamers, which are molecules made from RNA that can attach themselves to proteins. He has already identified one particularly promising aptamer, called B40, which attaches to gp120, an external protein of HIV. By disabling gp120, this aptamer can prevent HIV from entering target cells and establishing infection. To take full advantage of this finding, Dr. James plans to determine which section of the gp120 protein is blocked, in the hopes that he can glean information to not only optimize the function of B40, but also to help in the design of other drugs that might target gp120.

Nathaniel Landau, Ph.D.
Salk Institute for Biological Studies
La Jolla, CA
$90,000

Vif:APOBEC3G: assay and structure: In the two years since the discovery of its viral role in HIV infection, scientists have learned a lot about the interaction between APOBEC3G, a naturally-occurring protein that protects cells from HIV infection, and Vif, the HIV protein that prevents APOBEC3G from exerting its protective effects. Dr. Landau plans to collaborate with other researchers to generate three-dimensional images of these two proteins to describe how they interact. He will also develop tests that can be used to search for candidate drug compounds that could prevent their interaction and thus free APOBEC3G to repel HIV infection.

Jeremy Luban, M.D.
Columbia University
New York, NY
$90,000

Screen for human cDNAs that promote HIV-1 virion production: While HIV reproduces well in human cells, there is no other species in which the virus reproduces as efficiently. Dr. Luban will take advantage of this phenomenon by attempting to infect mouse cells with HIV. With each attempt, he will add single human genes to the mix to identify human genes that promote HIV reproduction that are present in human cells but absent in mice. Once such genes are identified, scientists will be able to explore the possibility of developing drugs that block the ability of HIV to use the gene products to its advantage. These would represent valuable new additions to the anti-HIV drug arsenal.

Pantelis Poumbourios, Ph.D.
St. Vincent’s Institute of Medical Research
Fitzroy, Australia
$90,000

Receptor induced conformational changes in gp120: inhibitor targets?: In order to enter and infect cells, HIV first makes contact with susceptible cells via its gp120 protein. Once contact is made, both the gp120 protein and the gp41 protein to which it is tethered undergo shape changes that bring the virus closer to the cell and ultimately allow the virus to fuse with and enter the cell. Dr. Poumbourios wishes to understand how gp120 and gp41 receive and respond to the signal that makes them change shape. If different strains of HIV all use the same shape-changing mechanism, the process might one day be inhibited by drugs that would also be slow to induce drug resistance.

Richard Roberts, Ph.D.
California Institute of Technology
Pasadena, CA
$86,302

Antibody mimetic inhibitors of HIV fusion: A rise in a patient’s level of HIV that uses the co-receptor CXCR4 often presages a progression to AIDS. Blocking the ability of HIV to use this co-receptor may delay AIDS progression, but designing drugs that simultaneously block CXCR4, while maintaining its normal, beneficial function in the immune system, has so far proven impossible. Dr. Roberts will search through a group of over 10 trillion molecules hoping to find candidate drugs that do just this, while also learning which are the important characteristics of a drug that would block the interaction between HIV and CXCR4 while leaving the receptor’s crucial favorable functions intact.

FELLOWSHIPS

Matjaz Barboric, Ph.D.
University of California, San Francisco
San Francisco, CA
$99,000
Mentor: Matija Peterlin, M.D.

Negative regulation of HIV-1 cellular co-factor P-TEFb: Once HIV inserts itself into the DNA of human cells, it begins reproducing by coordinating the interaction between its own genes and a number of virus and cell proteins, one cluster of which is known as P-TEFb. P-TEFb can interact with the appropriate section of HIV genes only after it is released from a larger complex of proteins. Dr. Barboric plans to more fully elucidate this chain of events with two ultimate goals: to furnish a model for understanding viral latency; and to provide information that might be useful in designing drugs that prevent the HIV reproductive cycle from starting.

Jayanta Bhattacharya, Ph.D.
University of Massachusetts Medical School
Worcester, MA
$99,000
Mentor: Paul Clapham, Ph.D.

HIV-1 envelope-gag interactions and assembly in lipid rafts: Before newly made virus particles can emerge from infected cells, the constituent parts are assembled inside the cell. Dr. Bhattacharya will investigate how the different viral components locate one another and position themselves appropriately within the whole virus. He is particularly interested in the process by which the viral surface protein gp41 incorporates itself into the virus and the role played by its interaction with another viral protein, Gag. By understanding this process more fully, Dr. Bhattacharya will be able to design tests that can find drug compounds to block HIV assembly, thus rendering the virus incapable of further rounds of infection.

Florence Brunel, Ph.D.
Scripps Research Institute
La Jolla, CA
$99,000
Mentor: Philip Dawson, Ph.D.

Structure based design of gp41 analogs for HIV-1 vaccines: Dr. Brunel will take advantage of recent research findings that describe the interaction between a section of the HIV protein gp41 and a number of antibodies, in order to design a vaccine that might successfully generate the same or similar antibodies. She will produce short protein segments (peptides) and optimize their structure and function to minimize the degree to which the peptides induce irrelevant antibodies, while maximizing the degree to which they induce antibodies that can neutralize most strains of HIV. The suitability of these peptides as a vaccine will then be assessed in rabbits.

Yegor Voronin, Ph.D.
Fred Hutchinson Cancer Research Center
Seattle, WA
$99,000
Mentor: Michael Emerman, Ph.D.

Relative fitness of early and late variants of SIV in vitro: Early in the course of HIV infection, the virus strains present in patients are typically less virulent than those that emerge after several years. Dr. Voronin is striving to understand how HIV evolves into a potent destroyer of the immune system, even in the face of drug therapy that maintains the virus at very low levels. He will develop test tube mixtures that closely mimic the conditions in the body that influence viral infection, and will compare the reproductive ability of different strains of the related virus, SIV, that appear early versus late in monkey infection.