Nature Study Pinpoints Mechanism that Controls AIDS

Left untreated, HIV almost always progresses to AIDS in humans, except in about one in 300 HIV-infected people who have an initial burst of viral replication, then control the virus and remain AIDS-free without the medications that have turned the disease from a fatal to a chronic one.

Understanding how these individuals, known as “elite controllers,” suppress replication of a virus that rapidly adapts to the human immune response is a mystery that David I. Watkins, Ph.D., professor of pathology, and his team explain in a seminal study published September 30 in the journal Nature. The study, “Vaccine-induced CD8+ T cells control AIDS virus replication,” determined that elite controllers suppress the virus by generating a potent “killer cell” CD8+ T response against just two or three small regions of the virus.

“By focusing on these selected regions the immune response successfully controls the virus,” said Watkins, who with his colleagues at the Oswaldo Cruz Foundation in Rio de Janeiro, was recently awarded a $10 million grant from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases to develop an HIV vaccine from the yellow fever vaccine. “Understanding this mechanism may shed light on how to develop an effective vaccine to eradicate the global HIV/AIDS crisis.”

For the Nature study, Watkins and his collaborators, including the investigators in Brazil, home to the leading experts and producers of the majority of the world’s supply of yellow fever vaccine, set out to pinpoint the link between known genetic determinants and the phenomenon of HIV control. As Watkins explained, about 70 percent of elite controllers have one of two genetic determinants, but not all people with those gene types control virus replication after HIV infection. So the critical question was: What is the link between the genetic determinant and the phenomenon of control?

To find the answer, Watkins and his team performed a simple experiment using an animal model that effectively mimics the naturally occurring elite controller phenomenon in humans. Approximately half of animals that express a particular genetic determinant will control the replication of the monkey equivalent of HIV without any drug intervention. The investigators vaccinated these animals that expressed this genetic determinant to induce CD8+ T killer cell responses against three small regions of the virus. The result: all vaccinated animals became elite controllers.

“What this likely means is that in humans these CD8+ T killer cells directed against small regions of HIV are responsible for control,” Watkins said. “The next step is to find out why these particular killer cells are so effective.”

In addition to Watkins and his collaborators in Brazil, the Miller School’s Mauricio A. Martins, Ph.D., a post-doctoral associate in the Department of Pathology, was a co-author on the study. Other co-authors include researchers from the University of Wisconsin-Madison, the University of Minnesota, the University of Alabama at Birmingham, and the National Cancer Institute.

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