Fighting HIV with Genetics
By Jeffrey Laurence, M.D.
April 19, 2006—About a decade ago, amfAR-funded scientists, along with several other groups, demonstrated that an apparently harmless mutation in a human gene could protect the lucky few who inherit the altered gene from both parents from infection by most strains of HIV.
About one of every 50 Americans of European descent and two in every 50 Scandinavians inherit this mutation, delta32-CCR5, from both parents. It has not been seen in Africans or Asians. Those who carry the double mutation cannot be infected by AIDS viruses using the CCR5 protein--the most commonly used portal of cell infection.
This discovery proved to be of much more than just intellectual interest. It led to the design and clinical testing of several drugs that can mimic this genetic change, and should prove useful in treating those already infected. Impressive decreases in AIDS virus loads have already been documented in several large patient trials.
Actually, the delta32-CCR5 mutation is not totally without consequence. It does increase the risk of severe illness from a West Nile virus infection in both mice and humans. But that is a small price to pay for being protected from HIV. Indeed, discovery of the impact of this genetic change spurred inquiry into how other human genes or gene mutations might also protect against HIV and lead to development of other novel anti-HIV drugs.
For example, a human enzyme, APOBEC3G, can lethally "edit" HIV genes, as reviewed in a recent paper in the Journal of Biological Chemistry, co-authored by amfAR fellow Dr. Ya-Lin Chiu of UCSF. APOBEC3G would provide potent protection against HIV infection, but unfortunately, the HIV protein Vif normally circumvents this natural antiviral defense. The race is on to identify drugs that can block this Vif-APOBEC3G dance or prevent the natural inactivation of a form of APOBEC3G that does remain active against HIV, at least in "resting" or non-activated immune cells.
According to Dr. Steve O'Brien of the National Institutes of Health, who has done important work in this area of natural resistance factors against HIV, if one were to collect all that is known about how a person's genetic make-up either blocks an HIV infection or slows the progression from infection to AIDS, we would be able to explain less than 10 percent of the way genetics impacts HIV. Obviously much more work remains to be done.
Another amfAR-funded scientist, Dr. Richard Sutton of Baylor College of Medicine in Houston, appears to have brought us a step closer to defining these other genes. Writing in the April 2006 issue of the Journal of Virology, his group discovered that an impediment to HIV infection that occurs in mouse cells early in the virus’ life cycle can be overcome by a factor that resides on one of the 23 chromosomes in the human body, chromosome 2. The identity of that critical gene or genes on chromosome 2 is not yet known.
The Human Genome Project, completed in 2003, was an ambitious undertaking, recording all of the genes found in most humans. But the really hard work comes next, describing the functions of each of the approximately 25,000-30,000 human genes. That work will probably take decades clearly we are only seeing the tip of the iceberg in terms of the potential of genetics to yield dividends in treating and preventing AIDS as well as numerous other diseases.
Dr. Laurence is senior scientific consultant for programs at amfAR