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AIDS RESEARCH Mutation Reported With AIDS Vaccine News of the death of a monkey after the virus it harbored had escaped its vaccine-boosted immune system by mutation, was widely reported as an alarming follow-up to one of the most promising AIDS vaccine trials to date. But for researchers in the field, the results were anything but surprising. Viral escape is not uncommon in naturally occurring AIDS infections. In fact, Norman Letvin, principal investigator of the study in the Jan. 17 Nature and HMS professor of medicine, said, "This is exactly what we anticipated." The monkey was one of eight animals vaccinated with naked DNA encoding the Gag protein from simian immunodeficiency virus and the Env protein from HIV-1. The animals were challenged with a fatal simian-human immunodeficiency virus chimera (SHIV). The vaccine, typical of several scheduled for human testing or already in trials, was designed to elicit a vigorous protective cytotoxic T lymphocyte (CTL) response against viral antigen. In vaccinated animals, viral replication was suppressed to undetectable levels, giving them a significant survival advantage compared to sham-vaccinated monkeys. To date, seven of the eight animals are in good health. In the monkey that died, there was a "breakthrough" of viral replication at week 24 after infection. Postdoc and lead author Dan Barouch traced the resurgent viremia to a single nucleotide mutation in the Gag p11C epitope that arose sometime after week 14. The mutant antigen displayed a hundredfold decreased affinity for its MHC restriction element and a thousandfold lower recognition by CD8+ lymphocytes. In vitro, newly synthesized MHC molecules did not stay folded around the mutant antigen, literally allowing it to slip away. Within six weeks the mutant species had replaced the entire original viral population. The ensuing explosive growth in the altered species eventually led to clinical AIDS and the experimental monkey's death. The implications were clear. "These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years," wrote the authors. --Anne Mahon