Researchers find clues to AIDS virus mystery

Scientists working with monkeys at UW–Madison have discovered new evidence explaining why retroviruses such as HIV in people and SIV in rhesus monkeys are so variable and difficult for the body’s immune system to target and kill.

The finding, reported in the November issue of the scientific journal Nature Medicine, is another step toward the development of effective vaccines to prevent AIDS. David I. Watkins, professor of pathology and laboratory medicine, and two graduate students, David Evans and David O’Connor, conducted the research at the Wisconsin Regional Primate Research Center, one of eight U.S. primate centers supported by the National Institutes of Health.

A key finding: Killer cells called cytotoxic T lymphocyte cells (CTLs) likely play a greater role than previously thought in controlling infection in both humans and monkeys, says Watkins.

“Two important arms of the immune system that respond to infection are CTLs and antibodies,” Watkins explains. “However, the antibody response does not fully develop until much later. By contrast, the peak of the CTL response coincides with early control of virus replication.”

Within a month after infection, he says, enormous replication takes place. The virus infects and then copies itself within host cells, turning the host cells into “virus factories.” CTLs recognize these infected cells and destroy them, limiting viral spread.

Unfortunately, although a strong CTL response arises early, it ultimately fails to prevent progression to AIDS. Previous research has implied that HIV escapes the CTL response by replacing specific amino acids within regions of its own proteins that would normally be recognized by CTLs. The researchers tracked 10 of these regions, called epitopes, during the course of disease progression in rhesus monkeys. All 10 epitopes accumulated amino acid replacements. Many of the replacements either reduced or eliminated the CTLs’ ability to kill virus-infected cells.

“This supports the CTL escape hypothesis and underscores the importance of these killer cells in controlling viral replication,” Watkins says.

Further characterization of CTLs and the epitopes they recognize is critical to designing effective vaccines, he added. The Wisconsin Regional Primate Research Center is now developing a colony of genetically defined rhesus monkeys for more controlled AIDS research.

The Nature Medicine study represents collaboration between Watkins and Alessandro Sette at Epimune, Inc., of San Diego, Calif. The work also involved the Laboratory of Genetics and Department of Pathology and Laboratory Medicine at UW–Madison, Biomedical Primate Research Centre-TNO in the Netherlands, and the Institute of Molecular Evolutionary Genetics at Pennsylvania State University.