SCIENTISTS REVEAL NEW HIV VACCINE

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SCIENTISTS REVEAL NEW HIV VACCINE
20 February 2000 - University of Wisconsin-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.

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In achievement and prestige, the University of Wisconsin-Madison has long been recognized as one of America’s great universities. A public, land-grant institution, UW-Madison offers a complete spectrum of liberal arts studies, professional programs and student activities. Many of its programs are hailed as world leaders in instruction, research and public service.

The university traces its roots to a clause in the Wisconsin Constitution, which decreed that the state should have a prominent public university. In 1848, Nelson Dewey, Wisconsin’s first governor, signed the act that formally created the university, and its first class, with 17 students, met in a Madison school building on February 5, 1849.

From those humble beginnings, the university has grown into a large, diverse community, with about 40,000 students enrolled each year. These students represent every state in the nation, as well as countries from around the globe, making for a truly international population.

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The university achieves these ends through innovative programs of research, teaching and public service. Throughout its history, UW-Madison has sought to bring the power of learning into the daily lives of its students through innovations such as residential learning communities and service-learning opportunities. Students also participate freely in research, which has led to life-improving inventions from more fuel-efficient engines to cutting-edge genetic therapies.

Students, faculty and staff are motivated by a tradition known as the "Wisconsin Idea," described by UW President Charles Van Hise in 1904 as the compelling need to carry "the beneficent influence of the university ... to every home in the state." The Wisconsin Idea permeates the university’s work and helps forge close working relationships among university faculty and students and the state’s industries and government.

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