January 2008: amfAR Announces Inaugural Mathilde Krim Fellowship Awards for AIDS Research

Initiative signals amfAR’s renewed commitment to the future vitality and excellence of AIDS research

New York City–amfAR, the Foundation for AIDS Research, has announced that it will award more than $1 million in the inaugural round of Mathilde Krim Fellowships in Basic Biomedical Research.

Named in honor of amfAR’s founding chairman, Dr. Mathilde Krim, the Krim Fellowship program is a new research initiative created to support bright young scientists seeking innovative prevention and treatment solutions to HIV/AIDS. Since the early days of the epidemic, Dr. Krim has been a leading advocate of increased support for research on a disease that others have often preferred to ignore.

“amfAR was overwhelmed by the extraordinarily high caliber of proposals submitted,” said Dr. Rowena Johnston, amfAR’s vice president of research. “This response underscores the urgent need for support of young researchers who bring fresh ideas and vigor to the field and who represent the future of HIV/AIDS research.”

amfAR initiated the new program in response to the dwindling sources of support that are available to young scientists. Yet these same young researchers are often those with the most innovative and daring ideas – ideas that have breakthrough potential.

With Mathilde Krim Fellowship support, these future leaders of AIDS research will be searching for new drug treatment candidates, looking to optimize vaccine design, and even investigating barriers to a cure for HIV infection.

“amfAR has a long and proud history of supporting innovative research,” said amfAR CEO Kevin Robert Frost. “Our new Krim Fellowship program continues that tradition and takes it to a higher level. It is also a fitting tribute to the vision and unwavering commitment to research of our founding chairman.”

Since it was founded in 1985, amfAR has supported the early studies behind almost every significant breakthrough in the treatment of HIV/AIDS, including studies that were critical to the development of protease inhibitors, the powerful drugs that revolutionized the treatment of HIV/AIDS; pioneering research that led to the use of AZT to block mother-to-child transmission of HIV, resulting in the virtual elimination of this form of HIV transmission in the industrialized world; and studies that identified the essential role of the CCR5 co-receptor, on which one of the newest HIV therapies, maraviroc, is based.

amfAR will release grants annually under the Krim Fellowship program. Recipients of 2008 Fellowships are:

Ivan D’Orso, Ph.D./Mentor: Alan Frankel, Ph.D.
University of California, San Francisco, San Francsico, CA

HIV Tat-mediated transfer of P-TEFb to nascent RNA and its inhibition: In order to successfully reproduce, HIV must make full-length copies of its entire genome as well as copies of each of its genes. In order to ensure that full-length copies are made, the virus recruits a cell protein, P-TEFb, which interacts with a segment of the virus called Tat. Dr. D’Orso plans to elucidate the precise details of the process whereby Tat and P-TEFb bind together and the structure of these protein complexes. Understanding the process of assembly and the shape taken by these proteins when they are bound together will help point towards potential therapies aimed at disrupting the vital relationship between the two proteins.

Felipe Diaz-Griffero, Ph.D./Mentor: Joseph Sodroksi, M.D.
Dana-Farber Cancer Institute, Inc., Boston, MA

Modulation of HIV-1 reverse transcription and integration by TRIM5: Successful infection requires that the virus undergo several transformations before inserting itself into the human DNA. Several proteins within human and animal cells can prevent HIV infection from occurring and are largely the reason most other animals cannot be infected with HIV. Dr. Diaz-Griffero plans to determine whether one such infection-blocking protein, TRIM5alpha from rhesus monkeys, can block the successful completion of HIV infection not only before but after the virus converts itself to DNA. Understanding the various ways in which HIV infection can be blocked may aid in the development of therapies that enhance these infection-blocking proteins in humans.

Kushol Gupta, Ph.D./Mentor: Gregory Van Duyne, Ph.D.
The University of Pennsylvania School of Medicine, Philadelphia, PA

Biophysical and structural studies of the HIV integrase-DNA complex: In order for HIV infection to take place and to initiate reproduction, HIV must insert itself into the human DNA of the cell it has infected. The process whereby it finds its way to the nucleus of the cell and inserts itself into the DNA is incompletely understood, though researchers know that the HIV DNA must bind to the HIV enzyme integrase as well as the cell protein LEDGF. Dr. Gupta plans to use an array of technologies to generate the first atomic-level illustrations detailing the ways in which these three components bind together to accomplish the integration of HIV DNA into human DNA.

Nolwenn Jouvenet, Ph.D./Mentor: Paul Bieniasz, Ph.D.
Aaron Diamond AIDS Research Center, New York, NY

Morphogenesis and storage of HIV-1 particles: As a final step in the process of reproduction, various components of newly made viruses gather inside the wall of the cell in which they are reproducing. From there, they are assembled into whole viruses that then either bud out of the cell or are absorbed into compartments inside the cell. It is suspected that these internal compartments that sequester the virus might contribute to the ability of the virus to persist in an infected person despite vigorous immune system and drug therapy attacks. Dr. Jouvenet will use sophisticated microscope technology to study the sequestration process and the circumstances under which the virus eventually buds out of the cell, ultimately boosting our understanding of the barriers to curing HIV infection.

Brandon Keele, Ph.D./Mentor: Beatrice Hahn, M.D.
University of Alabama at Birmingham, Birmingham, AL

Identification and biological characteristics of transmitted HIV-1: Within weeks of HIV infection, most individuals have begun to mount vigorous immune responses to attack the virus, and yet there is no documented case of infection ever having been cleared. Dr. Keele plans to characterize the rapid mutations that HIV undergoes during the first months of infection in order to evade destruction by the immune system. He will also investigate the dynamics of viral mutation when a person is infected with more than one virus variant, and how that may alter the ways in which the virus responds to the immune system. Understanding the dynamics between the virus and the immune system during acute infection will guide efforts to develop an AIDS vaccine.

Kara Lassen, Ph.D./Mentor: Jonathan Karn, Ph.D.
Case Western Reserve University, Cleveland, OH

Novel post-transcriptional mechanisms of HIV-1 latency and reactivation: The major barrier to eradicating and thus curing HIV infection is the ability of the virus to persist in infected cells in a latent state, thus avoiding destruction by the immune system or by antiretroviral therapy. This survival strategy is accomplished by the virus when it begins to make copies of itself, which remain in the infected cell’s nucleus. Dr. Lassen will investigate the mechanism whereby HIV can begin making productive copies of itself after this period of latency. Understanding how viral production can be reactivated will help researchers design strategies to cure HIV infection.

Bruno Marchand, Ph.D./Mentor: Stefan Sarafianos, Ph.D.
University of Missouri, Columbia, MO

Ultrapotent inhibitors of wild-type and multi-drug resistant HIV: Despite the availability of more than twenty antiretroviral drugs, patients often develop drug resistance to all currently available drug classes, including the two currently available types of reverse transcriptase inhibitors (RTIs). Dr. Marchand and his colleagues have discovered a new type of compound that blocks the reverse transcription process but differs chemically from existing RTIs. The new compound is effective against normal as well as drug-resistant virus and thus may be exceedingly useful in guiding efforts to devise new drug treatment strategies. Dr. Marchand will characterize more closely the mechanism of action of this new compound.

Morgane Rolland, Ph.D./Mentor: James Mullins, Ph.D.
University of Washington, Seattle, WA

Maintenance of drug resistance mutations and HIV-1 evolutionary adaptation: When HIV reproduces, mutated versions of the virus can arise that are less susceptible to anti-HIV drug therapy. There is a fitness cost to the virus, however, since mutated HIV generally reproduces less efficiently. Despite being weaker, drug-resistant mutant HIV can persist in individuals and be transmitted to others, thus perpetuating treatment difficulties. Dr. Rolland hypothesizes that when the virus mutates to avoid drug therapy, it simultaneously makes other mutations that strengthen its ability to reproduce, outweighing the weakening effects of the therapy-evasion mutations. Future developments in HIV drug therapy will be guided by the results of Dr. Rolland’s research.

Rogier Sanders, Ph.D./Mentor: Ben Berkhout, Ph.D.
Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands $125,000

Generation of stable HIV-1 Env trimers through virus evolution: AIDS vaccine development has been hampered by the difficulty in producing a protein in the lab that mimics proteins on the surface of HIV. Such proteins could theoretically be used to make an AIDS vaccine. Researchers until now have been plagued by difficulties in generating a three-part protein (trimer), such as that on the surface of the virus, that is stable and has regions on its surface that would encourage the immune system to make antibodies. These antibodies could then successfully target the virus for destruction. Dr. Sanders plans to address several of the challenges that have plagued these efforts so far. Researchers generally agree that an AIDS vaccine should generate appropriate antibodies in order to prevent HIV infection.

About amfAR:

amfAR, The Foundation for AIDS Research, is one of the world’s leading nonprofit organizations dedicated to the support of HIV/AIDS research, HIV prevention, treatment education, and the advocacy of sound AIDS-related public policy. With its freedom and flexibility to respond quickly to emerging opportunities and its determination to invest in cutting-edge science, amfAR plays a unique, catalytic role in accelerating the pace of HIV/AIDS research and achieving real breakthroughs. Funded by voluntary contributions from individuals, foundations, and corporations, amfAR has invested $260 million in support of its mission since 1985 and has awarded grants to more than 2,000 research teams worldwide.

For additional information about amfAR, The Foundation for AIDS Research, and the Krim
Fellowship, visit the amfAR website at amfarwebdev01.wpengine.com.

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