( this loss of Nef-mediated suppression...)HIV-1's high virulence might be an accident of evolution

, this loss of Nef-mediated suppression of T cell activation appears to have occurred twice, once in the ancestor of a group of viruses infecting Cercopithecus monkeys, and once in SIVcpz, the ancestor of HIV-1 which infects chimpanzees," noted study coauthor Paul Sharp, of the University of Nottingham, who is a leading expert in HIV and SIV evolution.

"What these viruses have in common is a vpu gene, not found in other SIVs, and so it's tempting to speculate that the presence of vpu is somehow causally related to the change in Nef function," Sharp added.

The findings expand on previous studies that found that nef-deficient SIV failed to cause symptoms in a monkey species normally susceptible to disease, Kirchhoff said. Rhesus macaques infected with the mutant virus had extremely low viral loads and "either no pathogenicity, or a markedly protracted disease course." Similarly, humans infected with nef-defective HIV-1 progress to disease symptoms slowly, if at all.

Several Nef functions were found to be likely contributors to the effect, including the gene's ability to get around the immune system.

"The gene was shown to be important for viral pathogenicity," Kirchhoff said. "It appeared that Nef was a 'bad guy' because it enhanced persistence and replication of the virus."

The new findings suggest the gene's role may be less black and white. "SIV Nef not only facilitates SIV persistence but may act as a 'rheostat,' allowing high enough levels of T cell activation to ensure sufficient viral replication and transmission, while at the same time preventing escalation of immune activation to levels that may be harmful to the host," the researchers said.

The results also raise the possibility that treatments that could carefully limit the immune system in infected humans--mimicking the tight balance maintained in the other primates--might offer a new approach to HIV therapy, Kirchhoff said.

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Source:Cell Press

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