May 23, 2003

D’Aquila receives unrestricted research grant

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Dr. Richard T. D’Aquila will lead the new HIV research center at Vanderbilt. (photo by Dana Johnson)

D’Aquila receives unrestricted research grant

Dr. Richard T. D’Aquila, Addison B. Scoville Professor of Medicine and professor of Microbiology & Immunology, has received a Bristol-Myers Squibb Unrestricted Biomedical Research Grant in Infectious Diseases. D’Aquila is free to apply the five-year, $500,000 award to any aspect of his research, which is focused on the biology of HIV infection during antiretroviral therapy.

“This is quite an honor,” said D’Aquila, who is also director of the division of Infectious Diseases. “I was delighted when I first learned I was being considered, and am thrilled that I was selected.”

The Bristol-Myers Squibb grant program provides no-strings-attached funding in six scientific fields, including cancer, cardiovascular diseases, metabolic diseases, neuroscience, and nutrition, in addition to infectious diseases. The unrestricted nature of the grants allows institutions to put the support where it is most needed and gives scientists the freedom to pursue uncharted paths.

“This kind of award is ideal for supporting research that is difficult to fund in other ways,” D’Aquila said. “What I’ll be using it for is to generate pilot data, that is, preliminary data that will contribute to applications for NIH or other foundational support of innovative research.”

Specifically, he intends to expand his research into areas new to his lab, including understanding how human genes play into the body’s response to anti-retroviral therapy in HIV-infected patients. Until now, he has concentrated his studies on how the virus changes in response to such drugs, leading in some cases to drug resistance.

“I’d like to understand how some of the HIV gene products interact with (the body’s) cellular gene products,” said D’Aquila. “Also, we need to learn more about cellular gene products that influence how well patients respond to antiretroviral drugs. If we could predict which drugs are going to be most effective for a specific individual, we could better manage treatment.”

He is already collaborating with several other Vanderbilt researchers to study how one category of cellular gene products, called drug transporters, influences response to HIV drugs. The job of these specialized cellular proteins is to recognize foreign substances in the cell, bind them up, and pump them out of the cell before they can do damage. The problem comes when these proteins recognize the anti-retroviral drugs as foreign and oust them before they have a chance to quash the virus.

Anti-retroviral therapy sometimes fails in patients even though there are no resistance mutations in their infecting viruses. D’Aquila suspects that those patients may have very active drug transporters. He plans to investigate whether the increased activity might be due to minor variations (polymorphisms) in the genes encoding the drug transporter proteins. Or, perhaps, if more of the proteins are being produced in response to either the drugs, the HIV infection itself, or to some environmental factor.

At a recent international scientific meeting, D’Aquila and his collaborators presented preliminary data showing that expression of certain drug transporters in cells from HIV-infected patients varies with antiretroviral drug treatment and its effectiveness. The team includes Dr. David W. Haas, associate professor of Medicine, Maria Pia DePasquale, Ph.D., research assistant professor of Medicine, John P. Donahue, Ph.D., research assistant professor of Medicine, and Dr. Todd M. Hulgan, instructor in Medicine. Dr. Richard B. Kim, associate professor of Medicine and Pharmacology, and Dr. Catherine C. McGowan, assistant professor of Medicine, are also collaborating with the team.

Most immediately, D’Aquila said, the award money will be used to hire additional personnel and to expand the Comprehensive Care Center/Vanderbilt patient specimen repository and databases that enable these research projects. The Comprehensive Care Center is an organization that serves HIV-infected individuals in Middle Tennessee, providing cost-effective, state-of-the-art medical care and facilitating the provision of related support services to these individuals and their loved ones. The Center is staffed by Vanderbilt’s Division of Infectious Disease and is a key component in the current expansion of the division’s translational research in HIV.

Over the longer run, the award will directly benefit clinical scientist trainees by involving them in cutting-edge research projects designed to explore novel and emerging hypotheses.

One such project involves studying a cellular gene product called CEM-15, identified just this past summer, that is a powerful suppressor of HIV replication. Vaccine and drug developers are looking to the discovery as a very promising way to suppress the ability of the virus to reproduce and infect cells. D’Aquila is collaborating with Dr. Alfred L. George Jr., Grant W. Liddle Professor of Medicine, to study whether genetic differences in CEM-15 influence how many infected cells lie dormant in patients who are responding well to treatment.

“One of the biggest problems we face right now,” he said, “is that even when our drug treatments work beautifully and patients are able to remain without any evidence of active virus replication for many years, there are still a small but appreciable number of latently infected cells that persist in the body, apparently for dozens of years.”

When the drugs are stopped, D’Aquila said, the cells provide a reservoir from which HIV can again start to replicate and “restart the clock on causing disease.” By understanding why some people have fewer latently infected cells than others, they hope to find ways to eradicate such viral strongholds so that a patient’s anti-retroviral therapy has an end-point rather than being a lifelong regimen. Curtailing therapy is highly desirable, he said, since there are “a lot of very bad consequences to long-term use of these drugs.”

D’Aquila is optimistic about how this monetary windfall will enhance his research efforts.

“The research that we can do with this grant might contribute eventually to some fairly dramatic changes and improvements in how we manage the therapy of HIV infection,” he said. “I am grateful that BMS recognizes the great opportunities here, and I’m hopeful that in the next five years we will accomplish some very important things.”

Bristol-Myers Squibb is a global pharmaceutical and related health care products company. Initiated 26 years ago, the grant program, through the Bristol-Myers Squibb Foundation, has committed more than $100 million to scientific research, awarding 240 grants to more than 140 institutions in 24 countries worldwide.