Possible key to slow progression toward AIDS identified
Washington: In a new study, a group of investigators may have uncovered the key to the variation in the speed of AIDS progression among slow progressors with a gene called HLA-B*57 (B57).
HLA-B*57 (B57) is an immune gene variant that is found in less than 5 percent of the general population but in 40 to 85 percent of slow progressors.
According to investigators from the Multi-Center AIDS Cohort Study (MACS), a killer T-cell immune response that occurs early on in HIV infection and targets a section — or epitope — of the HIV protein called IW9.
“Since the hope for a vaccine is that it would elicit immune control, the thought has been that understanding how B57 protection works would yield helpful lessons and principles for vaccine design,” Catherine Brennan, lead author of the study, said.
“There have been a lot of efforts to understand how the immune response to HIV in B57 carriers is superior to the response in non-B57 carriers, but it has been hard to nail anything down conclusively,” Brennan said.
HLA-B genes are known to work by activating killer T cells that recognize unique sections of proteins, or epitopes, but it has been a mystery which section or sections of HIV protein HLA-B57 and the killer T cells work through.
Previous research had largely focused on the killer T-cell response after several years of infection. However, Beth D. Jamieson, a professor of medicine at the Geffen School of Medicine and the study’s principal investigator, believes that the most critical responses are likely to occur early during infection, when the T cells are still strong and can reduce the number of places where HIV hides out in the human body.
Researchers have studied the immune response in the early months of infection, but since it is not easy to predict at early stages which people will ultimately become slow progressors, correlating early immune responses with long-term outcomes has been difficult.
“What made this kind of study possible for us is the Multicenter AIDS Cohort Study, which is an incredible longitudinal study,” Brennan said.
The MACS has been freezing blood samples every six months since 1984 from thousands of men either at risk of HIV infection or already infected.
“The size and duration of the study, along with the careful documentation of participant health and stewardship of frozen samples, allowed us to recover blood samples taken shortly after HIV infection from 14 HLA-B57 carriers with known infection dates and known long-term outcomes,” Brennan said.
“This allowed us to correlate early immune responses with long-term outcomes,” she said.
It was important to the researchers to compare only the killer T-cell responses among those with the B57 gene variant, instead of comparing the responses of those with and without B57. Although B57 carriers have, on average, much better prognoses than non-carriers, there is tremendous variability among the population, and not all do well, Jamieson said.
“Since possession of the B57 variant is not sufficient, we wanted to determine what specific immune events in B57 carriers are associated with immune control of the virus,” she said.
“We found that those who targeted the IW9 epitope early in infection had significantly longer times until onset of AIDS than those who did not. The finding that targeting of IW9 seems to be important is novel, as this epitope had been overlooked in many earlier studies of B57 and HIV,” Brenna added.
The study has been published in the Journal of Virology.