Identifying Vulnerabilities in HIV as New Drug Targets
By Jeffrey Laurence, M.D.
July 18, 2006—Recent work by amfAR fellow Dr. Jayanta Bhattacharya, under the mentorship of Dr. Paul Clapham at the University of Massachusetts Medical School, may point the way to the development of new types of anti-HIV medications.
Over the past decade, discovery of new drugs to disable key enzymes of HIV—reverse transcriptase and protease—has saved countless lives. Most recently Fuzeon, the HIV fusion inhibitor first tested by an amfAR researcher in 1993, has joined the armamentarium of anti-HIV drugs. Ongoing trials of additional experimental medications, to block HIV attachment to cells or disable another viral enzyme, integrase, offer additional hope for people with drug-resistant virus, or those suffering intolerable side effects of their current medications.
Writing in the June issue of the Journal of Virology, Dr. Bhattacharya and colleagues provide hope for yet another means of attacking HIV. They began by asking a very basic question: Once a cell is infected, how do the various sugar-protein components of the AIDS virus assemble into those tiny particles, or virions, capable of budding out of the cell as infectious agents? HIV has several classes of proteins that determine aspects of the virus' structure (e.g., Gag), function (e.g., Pol) and outer surface (e.g., gp120 and gp41). Bhattacharya and colleagues discovered that core Gag proteins of the virus must first bind to special parts of the viral coat protein gp41. This complex material is able to bind to "lipid rafts"—small groupings of cholesterol and lipids—on the surface of the cell the virus has infected. Such rafts are thereby co-opted to serve as platforms for assembly of mature HIV. AIDS viruses incapable of directing this assembly function were found to have mutations in critical parts of gp41.
Dr. Bhattacharya realizes that there is more work to be done before the best method of blocking this process, and thus the formation of infectious virus, can be designed. Where do the viral coat and core proteins first meet inside the cell? Does this interaction occur before or after binding to the lipid rafts? The answers to these questions should, in the concluding words of the authors, "help the design of strategies to prevent release of infectious virions."
Completing his fellowship, Dr. Bhattacharya has accepted a position at the National AIDS Research Institute in Pune, India. AIDS is a serious problem in India. While HIV prevalence may be low compared to the countries of sub-Saharan Africa, in terms of actual numbers India now has more HIV/AIDS cases than any country in the world.
Dr. Bhattacharya will join an important group in Pune, including another former amfAR fellow, Dr. Debashis Mitra, all working to develop new AIDS drugs that could alter the course of HIV worldwide.
Dr. Laurence is senior scientific consultant for programs at amfAR.