MADISON -- Scientists have shown for the first time, using a nonhuman primate model, that the AIDS virus avoids the body's strongest immune responses during the first few weeks of infection. The finding, which appears in the Sept. 21 issue of Nature, opens the door to new vaccine directions.
"We have discovered a potentially promising new approach to attack the AIDS virus," says David Watkins, professor of pathology and laboratory medicine at the University of Wisconsin-Madison.
"We have found that this early immune evasion allows the virus to sidestep a massive killer T cell response that occurs soon after infection," he added. "These results show that infected individuals do make immune responses that the virus cannot tolerate. The challenge will be to mimic these responses in an HIV vaccine."
Watkins, post-doctoral researcher Todd Allen and graduate student David O'Connor studied rhesus macaques infected with the monkey equivalent of HIV at the Wisconsin Regional Primate Research Center in Madison. Two weeks after infection and before the immune response fully developed, the virus remained unchanged from the stock used to infect the animals.
Shortly thereafter, the killer T-cell immune response that the researchers discovered began to combat the virus. Killer T cells are found throughout the body and are one of the immune system's most powerful weapons; they quickly and directly kill virally infected cells.
Four weeks after infection, the scientists could no longer isolate the original virus. Instead, a different virus predominated, one with changes in the region of the virus recognized by the immune response. They mapped this region to the small viral Tat protein, and showed that this Tat-specific killer T-cell response is the most potent early cellular immune response in these animals.
"The virus entirely escaped from the Tat-specific immune response within the first few weeks of infection," Watkins says. "The new virus was no longer recognized by the early Tat-specific killer T cell response. This is an example of Darwinian selection for viruses that evade immune responses and has many implications for novel vaccine approaches."
Until now, early killer T cell immune responses have been overlooked in the war against AIDS. By the time HIV infection is detected in humans, these fleeting, but effective, first lines of defense have already come and gone. Responses that arise later in infection may not be as successful at suppressing the virus.
Watkins believes that regions of the virus recognized by killer T cells during the acute-phase cellular immune response, such as this region found in Tat, might represent particularly effective regions of the virus for inclusion in an HIV vaccine. "If vaccines can induce these killer T cell responses before infection occurs, the opportunity for the virus to subsequently escape from these immune responses would be greatly reduced."
Scientists have previously shown that treatment of HIV-infected patients with AZT and other AIDS drugs often results in the selection of variant, drug-resistant viruses. This study demonstrates that early cellular immune responses also place selective pressure on the virus. The similar rates of selection in both cases lead the researchers to speculate that early killer T cell responses may be nearly as effective as antiretroviral drugs in controlling HIV. They have started to vaccinate monkeys with regions of the Tat protein that they have shown to be recognized by the killer T cells.
"This should induce a massive killer T cell response at the onset of infection," says Watkins. However, he cautions, "This virus has evaded nearly every vaccine-induced immune response to date. We would be surprised and delighted if the virus did not find a way around this Tat-specific immune response."
Collaborators on the study included Alex Sette from Epimmune Inc., a San Diego pharmaceutical company; Steve Wolinsky from Northwestern University, David Allison from Columbia University, Austin Hughes from The University Of South Carolina, Ron Desrosiers from the New England Regional Primate Research Center, and John Altman from The Yerkes Regional Primate Research Center.
The research was supported by the National Institute of Allergy and Infectious Diseases, the National Center for Research Resources, and the Elizabeth Glaser Pediatrics AIDS Foundation. The Wisconsin Regional Primate Research Center is one of eight primate centers supported by the National Institutes of Health.
-- Jordana Lenon (608) 263-7024, jlenon@primate.wisc.edu
NOTE TO PHOTO EDITORS: High-resolution images of Watkins and his lab are available for downloading at:
http://www.news.wisc.edu/newsphotos/watkins.html
Journal
Nature