February 2004: Grants Include Research on Natural Host Resistance Factors
The American Foundation for AIDS Research has awarded 11 grants and fellowships totaling more than $1 million to support scientists working to increase knowledge about HIV/AIDS, to improve methods of treatment and prevention, and to move the world closer to a possible vaccine.
“amfAR’s new funding again focuses on natural host resistance factors,” said Dr. Rowena Johnston, who directs Basic Research grant programs at amfAR. “The human body possesses natural defense mechanisms that the virus has, unfortunately, evolved to outwit. amfAR is funding scientists who are looking for ways to reinstate those natural defenses.”
Examination of natural host resistance factors was spurred by the observation that HIV replicates in few other animals.
“The human body possesses natural defense mechanisms that the virus has, unfortunately, evolved to outwit. amfAR is funding scientists who are looking for ways to reinstate those natural defenses.”—Dr. Rowena Johnston, Director of Basic Research
Because cells in most primates cannot support viral replication, scientists question why human cells can. Dr. Ya-Lin Chiu at the J. David Gladstone Institutes in San Francisco has been named an amfAR fellow to study APOBEC3G, one of these natural resistance factors.
Following on the heels of another amfAR grantee, Dr. Roberto Mariani, who described how the action of the APOBEC3G protein restricts HIV infection to humans, Dr. Chiu will observe how the HIV protein Vif dismantles APOBEC3G. Dr. Lionel Berthoux of Columbia University, another new amfAR Fellow, will investigate two less well-understood resistance factors, Ref1 and LV1.
Other new grantees continue the challenging work on an HIV vaccine. “One of the fundamental difficulties in developing a vaccine has been our inability to induce broadly neutralizing antibodies that target surface HIV proteins,” Dr. Johnston said. Dr. Julie Reitter, of the University of Massachusetts Medical School, will determine effective ways to neutralize gp41, one of the two proteins that appear on the surface of the virus.
amfAR’s next round of targeted research grants and fellowships includes a focus on mucosal transmission to gain an understanding of how HIV may infect women and men differently. Letters of intent for the next round are due March 9, 2004.
TARGETED FELLOWSHIPS: NATURAL HOST RESISTANCE FACTORS IN HIV INFECTION
Lionel Berthoux, Ph.D.
New York, NY
Sponsor: Jeremy Luban, M.D.
Cloning of Ref1 and Lv1 retroviral restriction factors: For a number of years, scientists have known of the existence of factors, termed Ref1 and Lv1, inside the cells of humans and other mammals that can prevent retroviruses, like HIV, from reproducing. Dr. Berthoux will use a number of different techniques to attempt to identify the particular gene(s) responsible for the ability of Ref1 and Lv1 to prevent the successful reproduction of these viruses, in which part of the cell the antiviral action takes place, and will further characterize the mechanisms by which this block is achieved.
Ya-Lin Chiu, Ph.D.
J. David Gladstone Institutes
San Francisco, CA
Sponsor: Warner Greene, M.D., Ph.D.
Assembly of large APOBEC3G-RNA complexes – A target for Vif?: The HIV protein Vif assists in HIV reproduction by helping the virus to overcome a natural anti-virus defense in human cells called APOBEC3G. Dr. Chiu will investigate how APOBEC3G is synthesized in human cells, with a view to discovering how and when Vif interacts with and overcomes this defense mechanism. An understanding of this interaction will help her and research colleagues to find a drug to reinstate APOBEC3G’s antiviral activity.
Ayna Alfadhli, Ph.D.
Oregon Health and Science University
Sponsor: Eric Barklis, Ph.D.
HIV Gag protein interactions: In order for a virus particle to be infectious, its core, consisting of multiple Gag proteins, must be assembled properly. Each Gag protein must interact appropriately with other Gag proteins as well as proteins from the host cell to form a strong core structure. Dr. Alfadhli plans to study the formation of the viral core in depth, to determine which parts of the Gag protein are responsible for regulating the various protein interactions that result in a functional virus core.
Oliver Lenz, Ph.D.
Molecular Laboratories, EMBL
Sponsor: Winfried Weissenhorn, Ph.D.
Structural analysis of HIV gp41 in complex with neutralizing antibodies: The design of a vaccine that can prevent HIV infection from taking hold will require that scientists find a way to induce broadly neutralizing antibodies that could destroy the wide range of strains of HIV found around the world. One region of the virus that is similar between viral strains is an external protein called gp41. Dr. Lenz plans to gather more information concerning the structure of gp41, in particular how it might interact with antibodies, as a step toward developing a widely applicable AIDS vaccine.
Ryan Troyer, Ph.D.
Case Western Reserve University
Sponsor: Eric Arts, Ph.D.
HIV-1 fitness at acute infection: Much of the difficulty in studying factors that influence disease progression in HIV-positive people stems from our uncertainty that what happens inside the body is reflected accurately by experiments in the test tube. Dr. Troyer hypothesizes that how well the virus reproduces, how many different strains are present, and the immune response mounted by the patient all determine how fast disease progression occurs. He plans to use blood samples from patients at different stages of HIV disease to make measurements of each of these factors in the test tube to determine how well they correspond to the stage of disease in the patients.
GENERAL RESEARCH GRANTS
Debasish Chattopadhyay, Ph.D.
University of Alabama at Birmingham
Chemotherapy of opportunistic infections in AIDS: Dr. Chattopadhyay will continue his amfAR-funded work looking for new treatments for opportunistic infections in AIDS, including cryptosporidiosis and toxoplasmosis. He is looking at several enzymes that are present in both humans and these parasites, looking for key structural differences that might give clues as he searches through chemical libraries for new therapies for opportunistic infections.
Nancy Haigwood, Ph.D.
Seattle Biomedical Research Institute
Novel HIV vaccines using virus-like protein scaffold: Dr. Haigwood is investigating the use of a technology she and colleagues modified as a novel vaccine strategy. The technology is based on the protein scaffold of an enzyme complex from the bacterium Bacillus stearothermophilus, and is engineered to display a variety of HIV proteins which stimulate the immune system to generate a response against them. Experiments in mice appear promising so far – Dr. Haigwood plans to expand the number of HIV proteins tested and compare the effectiveness of different preparations in mice.
Beth Jamieson, Ph.D.
University of California, Los Angeles
Los Angeles, CA
Prior antigenic exposure and HIV disease progression: As with other characteristics, people inherit different patterns of immune system responsiveness. HIV-positive people who do not progress to AIDS within the expected time are often characterized by an immune system responsiveness known as HLA-B*57. While much is known about these people years after initial infection, Dr. Jamieson plans to study them before and soon after infection. Learning how it is these people initially respond to HIV may help researchers design an AIDS vaccine.
Rupert Kaul, M.D., Ph.D.
University of Toronto
Sexually transmitted infections and host immune control of HIV-1: The presence of a sexually transmitted infection (STI) has been shown to increase the chance that HIV will be transmitted. Dr. Kaul will investigate whether the presence of an STI also affects how well a person’s immune system responds to the infection, as well as disease course. These factors will be studied in a group of Kenyan female commercial sex workers. The results may help to influence efforts to address STIs as part of HIV prevention efforts.
Julie Reitter, Ph.D.
University of Massachusetts Medical School
Membrane topology of the cytoplasmic tail of HIV-1 envelope: The most effective vaccine strategy to prevent HIV infection would involve generating broadly neutralizing antibodies, possibly against the viral protein gp120. Efforts so far have not been successful, but Dr. Reitter plans to determine whether targeting another protein, gp41, might prove more effective. She will investigate the structure of this protein, especially its tail, most of which is found inside the virus, but parts of which are exposed on the virus’s surface. Her findings may help researchers design a more effective AIDS vaccine.
Simon Swingler, Ph.D.
University of Massachusetts Medical School
Macrophage activation by Nef and its impact upon viral transmission: Anti-HIV therapy is unable to entirely eliminate HIV from the body because of the ability of the virus to establish reservoirs that cannot be attacked by drugs. The viral protein Nef contributes to the establishment of reservoirs by enabling inactive cells to become infected. Dr. Swingler plans to study more extensively exactly how Nef achieves this, especially as it interacts with proteins found in cells. Knowing how reservoirs are established will allow scientists to pursue ways to prevent their formation.