June 21, 1006 (AIDSmeds)—HIV's ability to damage the human immune system mightamount to an accident of evolution, notably the loss of the protectivefunction of a viral protein called Nef. Like HIV in humans, relatedstrains of simian immunodeficiency virus (SIV) are rampant among manyspecies of monkeys. Unlike HIV in humans, many primates infected withSIV don't experience immune suppression or suffer the symptomsassociated with AIDS. The evidence, published by an international teamof researchers in the June 2006 issue of Cell, is the first to offer an explanation for this striking difference.

Thegroup found that a viral protein known to help the virus evade theimmune system, thereby allowing the SIVs that infect monkeys to persistand multiply with high efficiency, also has a protective role in thehost immune system. The SIV Nef protein ratchets down the activation ofT-cells following infection in primates, thereby limiting the harmfuleffects that can be caused by chronically strong immune activation.

Whilechronically strong immune activation may seem like a good thing when itcomes to fighting HIV infection, it ends up causing the death of manyT-cells and ultimately exhausts the immune system – two factors thatcan lead to AIDS.

The HIV Nef protein, and those ofits closest related simian viruses, however, lack this protectivefunction, leaving those infected susceptible to the heightened immuneactivation associated with progression to AIDS, according to the newresearch.

"Nef-mediated suppression of T-cellactivation is a fundamental property of primate lentiviruses thatlikely evolved to maintain viral persistence in the context of anintact host immune system," Dr. Frank Kirchhoff of the University ofUlm in Germany said. "The findings suggest that the gene function waslost during viral evolution in a lineage that gave rise to HIV-1 andmay have predisposed the simian precursor of HIV-1 for greaterpathogenicity in humans."

"Heightened immuneactivation is the only clear-cut difference between pathogenic andnon-pathogenic infections with the immunodeficiency viruses," Dr.Kirchhoff added. "The observed difference in Nef function may provide,for the first time, a mechanism to explain why many monkey speciesnaturally infected with SIV do not develop disease."

Studycoauthor Dr. Beatrice Hahn of the University of Alabama has previouslyshown that the two forms of HIV that infect humans originated fromrelated SIVs found in different species of African primates (see related news article).HIV-1 – most closely related to an SIV strain found in chimpanzees – isthe more virulent of the two human strains and the source of themajority of HIV infections throughout the world. The less pathogenicHIV-2 evolved from a virus that infects long-tailed relatives ofbaboons called sooty mangabeys. While HIV and SIV strains all infectT-cells that are critical for a functional immune response, SIV usuallydoes so without causing serious damage in their natural primate hosts.

Ofmore than 30 SIVs that have been molecularly characterized, all encodea Nef gene. However, information about the gene's function has comefrom studies involving the HIV-1 version of Nef. In turn, Dr. Kirchhoffand his group examined Nef genes taken from a variety of SIV types.

Accordingto the research conducted by Dr. Kirchhoff's group, Nef variants fromthe great majority of primate SIVs, including the less virulent humanstrain HIV-2, suppress the expression of a receptor normally found onthe surface of T-cells, making the immune cells less responsive toactivation. In contrast, the Nef gene of HIV-1 and a subset of closelyrelated SIVs failed to limit T-cell activation and death.

"Intriguingly,this loss of Nef-mediated suppression of T cell activation appears tohave occurred twice, once in the ancestor of a group of virusesinfecting Cercopithecus monkeys, and once in SIVcpz, the ancestor ofHIV-1 which infects chimpanzees," noted study coauthor Dr. Paul Sharp,of the University of Nottingham, who is a leading expert in HIV and SIVevolution.

"What these viruses have in common is a Vpugene, not found in other SIVs, and so it's tempting to speculate thatthe presence of Vpu is somehow causally related to the change in Neffunction," Dr. Sharp added.

The findings expand onprevious studies that found that Nef-deficient SIV failed to causesymptoms in a monkey species normally susceptible to disease. Otherresearchers have reported in the past that rhesus macaques infectedwith the Nef-deficient virus had extremely low viral loads and limitedevidence of disease progression. Similarly, humans infected withNef-defective HIV progress to disease symptoms slowly, if at all.

Whilealtering HIV's Nef gene may not be a therapeutic possibility for thoseinfected with the virus, these results – along with research conductedby several other teams – suggest the use of treatments that couldcarefully limit immune system activation in humans. This, Dr. Kirchhoffsays, would mimic the tight immune system-virus balance seen innon-human primates.

"A strong immune response can begood in the short term, but if sustained for a long time as in thosewith HIV, it can exhaust the immune system," Dr, Kirchhoff said. "Ifyou could somehow dampen the response, it might effectively convert thecondition to the more chronic, asymptomatic infection seen in monkeys."