Integrase: A New Word in the Fight Against HIV
By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
March 26, 2007—Integrase, an enzyme critical to the life cycle of HIV, burst into headlines around the world recently when findings reported at the Conference on Retroviruses and Opportunistic Infections held in February in Los Angeles indicated that a drug called raltegravir, which targets integrase, is markedly effective against drug-resistant HIV.
amfAR grantee Dr. Paul Bieniasz of the Aaron Diamond AIDS Research Center in New York, writing in the February 2007 issue of the Journal of Clinical Investigation, describes a different way of attacking the very same integrase enzyme. The work brings to light an entirely new aspect of the interaction between viral proteins, in this case integrase, and the proteins of the human cell that the virus is invading. It also further illustrates a general principle: evolution has provided cells, including those of humans, with key genes and proteins whose major, perhaps only, function is to fight off infection with retroviruses such as HIV.
In his commentary, Dr. Bieniasz reviews the work of former amfAR grantee Dr. Jielin Zhang and associates of Harvard Medical School. They found that a normal human protein, p21, can suppress the vulnerability of certain cells to HIV infection. p21 appears to have a direct effect on invading virus. It binds to a complex of virus proteins, key among them being integrase, and forces HIV to make genetic copies of itself in the form of DNA circles rather than the usual linear format. These circles are unable to join or “integrate” into the human cell’s DNA, and the virus’ genes die off.
p21 appears to be the newest type of host restriction factor—a product of host genes which impedes the growth of HIV. In his amfAR-funded research, Dr. Bieniasz works with two other such restriction factors, TRIM and APOBEC3G. In the search for new therapies, scientists are striving to understand how these key elements might be amplified or modified to overcome self-defense counter-attacks by HIV.
Another amfAR-supported grantee, Dr. Martin Markowitz, also of Aaron Diamond, performed the first clinical studies of the drug raltegravir, which is in the final stages of clinical testing. Raltegravir has received “fast track” status from the FDA, meaning data concerning its efficacy will be reviewed by that agency in the coming months. Most experts expect that it will be available to patients in the next year or so. This should promise many people with HIV/AIDS “the opportunity for a new life,” according to AIDS scientist Eric Daar of UCLA.
Dr. Laurence is amfAR’s Senior Scientific Consultant. Dr. Johnston is amfAR's Vice President, Research.