June 2003: Grants Include Research on Natural Host Resistance Factors
In June 2003, amfAR announced 16 grant and fellowship awards totaling nearly $1.5 million for basic research looking at ways to fight, and ultimately eliminate, HIV/AIDS. Nearly $300,000 was awarded for research on natural host resistance factors. Other projects will explore a wide variety of biomedical research on HIV/AIDS, including viral reservoirs and latency, immune reconstitution, and vaccines.
Half of the awards were two-year amfAR fellowships which enable young researchers to conduct original studies under the guidance of experienced senior scientists.
The funded projects were selected from among nearly 180 letters of intent submitted in response to amfAR's February 2003 request for proposals (RFP). The RFP called in particular for research on natural host resistance factors—genetic elements present in other species that prevent productive HIV infection from taking place. Cells from almost all non-human primates, or any other species, are unable to support the replication of HIV. A number of the new amfAR grantees and fellows seek to understand these natural host resistance factors and how they interfere with intracellular steps in viral replication. An understanding of these resistance factors may lead to new ways to treat or prevent HIV infection.
For example, Dr. Richard Sutton, Assistant Professor of Molecular Virology and Microbiology at the Baylor College of Medicine, has been funded to insert monkey genes into human cells in a test tube to observe which monkey genes render cells resistant to infection. Dr. Sutton will examine these genes that cause resistance to determine how they work and how these mechanisms might be used in novel HIV therapies.
“We are particularly heartened by the increasing number of international scientists seeking basic research support from amfAR,” said Dr. Jeffrey Laurence, amfAR’s Senior Scientific Consultant for Programs and Director of AIDS Virus Research at Cornell University’s Weill College of Medicine. One international grantee, Dr. Antonin Holy, Senior Research Scientist at the Institute of Organic Chemistry and Biochemistry in Prague, will modify two compounds he discovered, both FDA-approved therapies, to create new formulations that fight resistant virus. “Dr. Holy’s research may extend the treatment options of patients who have become resistant to current anti-HIV therapies,” Dr. Laurence said.
TARGETED GRANTS AND FELLOWSHIPS: NATURAL HOST RESISTANCE FACTORS
Theodora Hatziioannou, Ph.D. — Fellowship
Aaron Diamond AIDS Research Center
New York, NY
Sponsor: Paul Bieniasz, Ph.D.
Mechanism of HIV-1 inhibition by host factors: A gene in mice can slow the growth of murine leukemia virus, a retrovirus like HIV. Similar genes are suspected to exist in humans that would slow or prevent the growth of HIV were it not for the interaction of the virus with a cell protein called CyclophilinA. The mechanism by which the as yet unidentified gene(s) might slow the growth of HIV is not well understood, although it is generally believed to involve a block of the viral protein Capsid. Dr. Hatziioannou will undertake studies aimed at increasing our understanding of this process. She will also attempt to identify the human gene suspected of the ability to block HIV.
Richard Sutton, M.D., Ph.D. — Grant
Baylor College of Medicine
Genetic screen for HIV simian resistance factor: Most monkeys, unlike humans, cannot be infected by HIV. In order to determine which monkey gene(s) may be responsible for their resistance to infection, Dr. Sutton plans to insert monkey genes, one at a time, into human cells in a test tube. Those human cells will then be exposed to HIV. Most cells will become infected, but those that are resistant to HIV infection presumably contain a monkey gene that prevents infection. Dr. Sutton hopes to determine exactly when, how and under which circumstances those genes can prevent HIV infection, and whether these findings can be used to develop new therapies to treat HIV/AIDS.
Francisco Navarro, Ph.D. — Fellowship
La Jolla, CA
Sponsor: Nathaniel Landau, Ph.D.
Identification of antiviral primate genes: Several factors are believed to exist that might slow or stop the reproduction of lentiviruses like HIV, and are believed to be responsible for the inability of HIV to grow in most primate species outside of humans. Dr. Navarro plans to transfer genes from monkey cells into human cells in a test tube. He will search for those genes that render human cells inhospitable to HIV. Once he has identified these genes, he will examine the mechanism whereby HIV is inhibited. Information gleaned from these studies will help scientists develop new therapeutic strategies to slow or prevent the growth of HIV.
TARGETED GRANTS AND FELLOWSHIPS: NOVEL VIRAL AND CELLULAR TARGETS
Antonin Holy, RNDr., Ph.D., Dr.Sc. — Grant
Institute of Organic Chemistry and Biochemistry
Prague, Czech Republic
New acyclic nucleoside phosphonates for AIDS therapy: Dr. Holy discovered the compounds that led to the development of two nucleotide reverse transcriptase inhibitors, Viread (to treat HIV) and Hepsera (to treat hepatitis), which were approved by the FDA in 2001 and 2002. He plans to continue investigating the same family of compounds, making modifications in the structures of a variety of the compounds, in order to produce improved versions of the compounds. He hopes that the newly synthesized compounds may be effective at combating virus that has become resistant to other currently available drugs.
Peter Prevelige, Ph.D. — Grant
University of Alabama at Birmingham
Discovery of inhibitors of HIV assembly and maturation: When developing new anti-HIV drugs, scientists aim to address drug resistance and the need to target the virus while leaving the host cells intact. Dr. Prevelige is searching through thousands of compounds for compounds that attack the viral protein Capsid. Capsid may represent an excellent target for anti-HIV drugs because it mutates at a lower rate than other HIV proteins, decreasing the chance that drug resistance will develop. In addition, because Capsid shares less similarity to human proteins than viral enzymes (the targets of almost all current therapeutics), anti-Capsid drugs may be less toxic. Dr. Prevelige has identified several promising leads and plans on characterizing those compounds more fully.
Michael Root, M.D., Ph.D. — Grant
Thomas Jefferson University
Discovery of small peptide inhibitors of HIV-1 gp41: Recently, the FDA approved the first member of a new class of anti-HIV drug, known as Fuzeon, a fusion inhibitor. (amfAR Fellow Dr. Carl Wild discovered the anti-HIV properties of this inhibitor in 1993.) One of the drawbacks of Fuzeon is the need to self-inject the drug twice per day. Dr. Root is working towards the development of a fusion inhibitor that can be administered orally. He has developed a method for searching through a large number of peptides (small proteins) similar to Fuzeon. Once he has found several that are effective against HIV, he will study their structure, providing valuable clues regarding the eventual design of non-peptide fusion inhibitors that can be taken by mouth.
Sachchidanand, Ph.D. — Fellowship
Mount Sinai School of Medicine
New York, NY
Sponsor: Ming-Ming Zhou, Ph.D.
Chemical inhibitors for the HIV Tat/PCAF BRD complex: Dr. Sachchidanand and colleagues recently discovered that in order for HIV reproduction to be initiated, the viral protein Tat must interact with a protein found in the host cell called PCAF, which normally functions to help convert human genes into human proteins. He will use nuclear magnetic resonance to define the structure of this interaction, and plans to use the information to design chemical inhibitors that would bind to PCAF, preventing its interaction with Tat and ultimately preventing HIV from reproducing. The advantage of targeting a host protein is that drug resistance is less likely to develop than with drugs that target viral proteins.
VACCINE RESEARCH GRANTS
Rosa Cardoso, Ph.D. — Fellowship
Scripps Research Institute
La Jolla, CA
Sponsor: Ian Wilson, Ph.D., D.Sc.
Structural basis of antibody neutralization on HIV-1: The failure so far of scientists to develop an AIDS vaccine is partly due to an incomplete understanding of how infection by viruses lead to the formation of antibodies that destroy them, and more particularly, why this process usually fails in the case of HIV. Dr. Cardoso plans to study those regions of HIV’s two surface proteins, gp120 and gp41, that can induce the formation of antibodies. Specifically, she plans to determine the structure of these regions as they bind with antibodies, in order to learn more about how to design a vaccine that could induce antibodies that would ultimately destroy HIV.
Ralph Pantophlet, Ph.D. — Fellowship
Scripps Research Institute
La Jolla, CA
Sponsor: Dennis Burton, Ph.D.
Sugar-coated gp120s as potential HIV vaccinogens: HIV has devised a number of strategies to avoid being detected and destroyed by the immune system. For example, it hides sections of its outer proteins (notably gp120) behind a sugar coating, thereby tricking the immune system into making antibodies that do not destroy the virus, while at the same time preventing an effective immune response. Dr. Pantophlet is taking a novel approach to the design of an AIDS vaccine - he will add sugars to the gp120 protein to hide those sections of the protein that are used by the immune system to make ineffective antibodies, and unmask those sections of the protein that might be used to make effective antibodies. Results may help vaccine development efforts.
Oliver Hartley, Ph.D. — Grant
University of Geneva
Using phage display to develop novel HIV inhibitors: In order for HIV to enter and thereby infect cells, it must interact with two proteins on the surface of target cells, its receptor CD4, and a co-receptor, most often CCR5. Dr. Hartley is searching for compounds that could block CCR5 and thus prevent HIV infection, especially by sexual transmission. He and his research team have developed a promising compound called PSC-RANTES, which they plan to improve by making the compound even more effective at preventing infection and ensuring that it does not have unwanted biological effects on other proteins. Dr. Hartley will test a number of variations of PSC-RANTES in an attempt to generate an optimized compound to be developed as an anti-HIV drug and/or microbicide.
RESERVOIRS AND LATENCY GRANT
Joseph Romeo, Ph.D. — Grant
San Francisco State University
San Francisco, CA
Transactivation potency of latent HIV-1 quasispecies: In order to make new viruses, one of HIV’s proteins, Tat, must interact with a section of its own genetic material, TAR. Dr. Romeo is exploring the hypothesis that mutated Tat and TAR, leading to abnormal interactions between the two, may underlie the formation of the HIV latent reservoirs that scientists know preclude the eradication of the virus. A better understanding of the process whereby latent reservoirs of virus are formed may help scientists to develop means to prevent their formation or to eradicate them once they have formed.
IMMUNE RECONSTITUTION GRANT
Patricia Fitzgerald-Bocarsly, Ph.D. — Grant
New Jersey Medical School
New Brunswick, NJ
Plasmacytoid dendritic cells in macaque SIV infection: HIV infection results in a wide range of abnormalities in immune system function. For example, a group of immune cells known as plasmacytoid dendritic cells normally produce an immune hormone called interferon-alpha, which in turn helps to destroy viruses and to orchestrate a broad immune response. These cells are known to become dysfunctional in HIV infection and may play a role in the progression to AIDS. Dr. Fitzgerald-Bocarsly plans to study the structure, function and location of these cells in healthy monkeys and to characterize changes that occur shortly after infection with SIV, the monkey equivalent of HIV, in order to better grasp changes that occur in HIV infection in humans.
GENERAL BASIC RESEARCH GRANTS AND FELLOWSHIPS
Kyle Bonneau, Ph.D. — Fellowship
University of California, San Francisco
San Francisco, CA
Sponsor: Jay Levy, M.D.
CAF effect on gene expression in infected CD4+T cells: There are a small number of HIV-infected people who, despite receiving no anti-HIV therapy, do not progress to AIDS for as long as 20 years or more after infection. Several groups of researchers believe there is a factor in a subset of immune cells in these people that can prevent the growth of HIV. (Dr. Jay Levy, Dr. Bonneau’s mentor and amfAR Board member, discovered the phenomenon). Dr. Bonneau plans to test the effects of the as yet unidentified factor on HIV-infected cells in a test tube. He will determine which genes in the HIV-infected cells are switched on or off. The findings may help researchers to identify this antiviral factor, and may point the way to new anti-HIV therapies.
Felipe Diaz-Griffero, Ph.D. — Fellowship
New York University School of Medicine
New York, NY
Sponsor: Dan Littman, M.D., Ph.D.
Sexual transmission of HIV - dendritic cells and HIV: Sexual transmission of HIV is the most common route of transmission worldwide. Understanding the cellular process whereby this occurs will be important for developing interventions that can prevent this from occurring, such as vaccines and microbicides. There are several types of immune cells, including dendritic cells and macrophages, found in close proximity to the vaginal wall that probably play an important role in bringing incoming HIV to the lymph nodes, where the virus can infect its target, a group of immune cells known as CD4+ T cells. Dr. Diaz-Griffero plans to study exactly how and where the dendritic cells internalize the virus, and how the virus is then ultimately delivered to the T cells.
Ladislau Kovari, Ph.D. — Grant
Wayne State University
Structure-function study of HIV-1 drug resistance: One of the major obstacles to successful long-term HIV therapy using existing drugs is the development of strains of virus that are resistant to drugs. Dr. Kovari plans to investigate changes in the structure of the viral enzyme protease that render protease inhibitors unable to counter the virus. He will collect samples from patients who exhibit resistance to protease inhibitors, as well as studying changes that occur in the protease enzyme over time in a single patient. These studies will help us to understand what processes the virus undergoes in order to evade protease inhibitors, and should allow scientists to design drugs that might be able to overcome this drug evasion strategy.
Jacqueline Reeves, Ph.D. — Fellowship
University of Pennsylvania
Sponsor: Robert Doms, M.D., Ph.D.
Viral and cellular factors impacting entry inhibition: Recently, the FDA approved the first entry inhibitor, a drug known as Fuzeon. The drug interacts with the viral surface protein gp41 and prevents HIV from entering target cells. However, as with other anti-HIV drugs, resistance can develop because of mutations in the virus. The amount of the coreceptor CCR5 on the surface of the target cell can also affect how well Fuzeon works. Dr. Reeves plans to study the interactions between these factors and to determine the consequences, for example on the ability to use other entry inhibitors that are currently being developed, after the virus has mutated to escape from Fuzeon.
amfAR’s Basic Research Program
The mission of amfAR’s Basic Research Program is to identify, fund, and advance innovative, creative, and timely research and research education projects in the basic science of HIV/AIDS. This goal is predicated on the belief that an understanding of the biology of HIV is the best means by which effective treatments and primary prevention measures, and an eventual cure, will be achieved.
Both amfAR grantees and fellows are selected through a rigorous process of peer review conducted by members of amfAR’s Scientific Advisory committee, a group of highly qualified professionals who volunteer their time and expertise to evaluate proposals on the basic of scientific merit, relevance, and promise.
For more information about amfAR's grant programs or to request inclusion on the mailing list for future RFPs, please contact:
American Foundation for AIDS Research
120 Wall Street, 13th Floor
New York, NY 10005-3902
Fax: (212) 806-1601