Understanding the Molecular Mechanisms of AIDS
By Jennifer Fisher Wilson
Through a confluence of career timing, research interest and a skill for tackling tough scientific puzzles, Dana H. Gabuzda ’79, associate professor in the department of cancer immunology and AIDS at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, has been at the cutting edge of AIDS research essentially from its beginning.
Gabuzda was a medical student at Harvard when young adults with Kaposi's sarcoma, Pneumocystis carinii pneumonia, and other rare conditions such as dementia and wasting started showing up at Massachusetts General Hospital during the early 1980s. By the time she became a medical intern in 1983, physicians had identified acquired immunodeficiency syndrome (AIDS), but they still struggled to understand its etiology. Even then, however, it was clear that “this was going to become a very important problem,” Gabuzda says, and she immediately became interested in the study of this new disease.
A year later, as a neurology resident, Gabuzda focused on neurological problems in AIDS patients — cognitive impairment, motor dysfunction, mood disturbances and, in some cases, severe dementia. Azidothymidine (AZT) and antiretroviral drugs were not yet used for treatment, and she remembers seeing patients “who were completely disabled and bedridden, and almost unable to speak because their brains were so severely affected by the disease.”
By the time Gabuzda had completed her residency in 1987, researchers had identified the human immunodeficiency virus (HIV). “It was clear that there were many important medical and scientific questions about HIV to be investigated through basic and clinical research,” she says. Gabuzda decided to continue working in this area, completing back-to-back fellowships in virology at Johns Hopkins University, Baltimore, and in basic AIDS research at the Dana Farber Cancer Institute. She then joined the faculty at Harvard Medical School and opened a lab at Dana Farber in 1991 that focused on researching HIV replication and pathogenesis.
Over the years, Gabuzda has emerged as one of the country’s top researchers in the molecular mechanisms of HIV, and the findings from her lab are contributing to new therapeutic strategies against HIV.
The VIF Connection
In 1991, scientists had already discovered that HIV infected the body by targeting certain immune cells — mostly T-cells — and co-opting them into replicating HIV. But they didn’t know what factors played a role in this process. Gabuzda started working with a little-studied HIV gene called “Vif”, short for virion infectivity factor. Over the course of the next decade, Gabuzda helped to elucidate Vif’s critical role in virus replication and spreading infection throughout the body.
Gabuzda’s work has contributed to a critical finding about Vif in 2002. She provided a cell line (CEM) expressing the APOBEC3G protein — a DNA-editing enzyme — to researchers at the University of Pennsylvania, Philadelphia, and King’s College, London, whose goal was to identify the mechanism that enables Vif to function. The King’s College researchers showed that Vif acts by inhibiting APOBEC3G — when APOBEC3G is not inhibited, it can stop the virus from replicating.
Gabuzda and other researchers have since shown that Vif binds to APOBEC3G and recruits it to the proteasome pathway, which degrades cellular proteins. Current research is focused on ways to block that interaction with small-molecule inhibitors. Gabuzda predicts that a drug based on this approach will be in development within the next few years. She is hopeful that such a drug would help control the disease, but she doubts that it will completely eradicate HIV from the body and cure AIDS. “It would become only another drug to be used in a multiple drug combination regimens, another way of suppressing the virus and prolonging the lifespan of HIV-infected individuals,” Gabuzda says.
New Avenues of HIV Research
In addition to her work with Vif, Gabuzda also conducts ongoing research on other aspects of the molecular mechanisms of HIV replication and pathogenesis and on the mechanisms of neurological disease in AIDS. She has co-authored more than 60 scientific articles and book chapters, and has presented her research findings at more than 60 conferences.
Gabuzda’s scientific career has benefited, she says, from the skills in communication and critical and analytical thinking that she developed during her undergraduate years at Bryn Mawr as a double major in English and music. She has also benefited from the opportunity to talk about work with her husband, Bruce Yankner, M.D., Ph.D., an Alzheimer’s researcher who is associate professor of neuroscience at Harvard Medical School and the Children’s Hospital, Boston.
Gabuzda expects to continue focusing on the intricacies of HIV replication and pathogenesis for at least the next 10 years — something she wouldn’t have expected earlier in her career. When protease inhibitors and combination therapies came out in the late 1990s, many people thought that HIV would be finally defeated. “There was a wave of optimism then, but looking back now, the idea that HIV was defeated was incredibly naive,” Gabuzda says. “Many more years of research are needed to understand the complicated biology of HIV and to develop vaccines and more effective drugs.”
Jennifer Fisher Wilson is the science writer for the Annals of Internal Medicine.