Two groups of people especially intrigue AIDS researchers: those who resist HIV infection despite repeated exposure to the virus and those who progress very slowly to AIDS after infection. Understanding what makes these individuals different could lead to new vaccines and treatments, and a study published this week in the early online edition of the journal AIDS brings scientists closer to that goal. It shows that a tiny variation in an immune system gene called RANTES can be a double-edged sword, substantially increasing one's susceptibility to HIV infection, but subsequently slowing down the disease's progress.
"This study offers the first genetic evidence that RANTES affects the risk of HIV transmission," says Dr. Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). "It also adds to the evidence that RANTES can slow the progression to AIDS in HIV-positive individuals, lending support to the search for a drug that mimics this gene's action."
"Some people don't become infected with HIV despite repeated, high-risk behavior. And some HIV-positive people progress rapidly to AIDS while others never do. We wanted to see what tips the scales," says immunologist Philip M. Murphy, M.D., the study's senior author. Dr. Murphy and his colleagues looked at known RANTES gene variations in HIV-positive and HIV-resistant individuals who participate in the Multicenter AIDS Cohort Study (MACS), a project funded by NIAID. The MACS is the largest continually monitored group of HIV-infected and at-risk people in the world. The genetic differences Dr. Murphy's team studied, called single nucleotide polymorphisms, or SNPs ("snips") for short, are the smallest possible, involving a change in just one base pair, or "rung," of the DNA ladder.
Still, these tiny SNPs can have a big impact. One such SNP appears significantly more often in HIV-positive than in HIV-resistant individuals. In fact, the scientists established that this SNP, which increases the activity of the RANTES gene, is associated with up to twice the risk of HIV infection. Paradoxically, individuals with this SNP who become infected with HIV take about 40 percent longer to develop AIDS.
How can the same SNP make people more likely to become infected with HIV but more resistant to the onset of AIDS? "At first blush it doesn't make sense," says David McDermott, M.D., the study's lead author, "but nothing involving HIV is simple."
Dr. McDermott offers a tentative explanation: the RANTES gene makes an immune system molecule also called RANTES, and the SNP in question causes the gene to make more. The normal function of the RANTES molecule is to cause inflammation, which opens up the spaces between cells, allowing infectious agents like HIV easier entry into the body. That is how RANTES can increase the likelihood of HIV infection. But to stimulate inflammation, RANTES must attach to the same receptors on the surfaces of T cells that HIV uses to grab hold of and gain entry into those cells. In effect, RANTES "elbows" HIV out of the way, forcing the virus -- once it has entered the body -- to work harder to jump from cell to cell and thereby spread.
RANTES seems to hinder HIV so effectively, at least in the test tube, that several companies are trying to develop a RANTES-based drug to slow the progression rate of HIV. "The results of our study support those efforts, but researchers must remember that higher RANTES levels may increase the likelihood of acquiring HIV," Dr. McDermott says.
Ultimately, understanding all the genetic variations that interact to affect one's response to HIV will one day allow doctors to create genetic profiles that quantify a person's susceptibility to the virus, Dr. Murphy says. Larger genetic variations are also known to affect how one responds to HIV, such as the previously discovered CCR5(32 alteration, which prevents the T-cell receptors that HIV uses from being made in the first place. This change makes one extremely resistant to the disease. But Dr. Murphy cautions that people should not think themselves immune. "If you stand in the way of a speeding truck," he says, "the risk of death is very high."
- DH McDermott et al. Chemokine promoter polymorphism affects risk of both HIV infection and disease progression in Multicenter AIDS Cohort Study. AIDS 14(17):2671-78 (2000).