Treatment News : HIV's Wicked Ways: An Accident of Evolution? - by Tim Horn

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June 21, 2006

HIV's Wicked Ways: An Accident of Evolution?

by Tim Horn

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

The group found that a viral protein known to help the virus evade the immune system, thereby allowing the SIVs that infect monkeys to persist and multiply with high efficiency, also has a protective role in the host immune system. The SIV Nef protein ratchets down the activation of T-cells following infection in primates, thereby limiting the harmful effects that can be caused by chronically strong immune activation.

While chronically strong immune activation may seem like a good thing when it comes to fighting HIV infection, it ends up causing the death of many T-cells and ultimately exhausts the immune system – two factors that can lead to AIDS.

The HIV Nef protein, and those of its closest related simian viruses, however, lack this protective function, leaving those infected susceptible to the heightened immune activation associated with progression to AIDS, according to the new research.

"Nef-mediated suppression of T-cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system," Dr. Frank Kirchhoff of the University of Ulm in Germany said. "The findings suggest that the gene function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans."

"Heightened immune activation is the only clear-cut difference between pathogenic and non-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 species naturally infected with SIV do not develop disease."

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

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

According to the research conducted by Dr. Kirchhoff's group, Nef variants from the great majority of primate SIVs, including the less virulent human strain HIV-2, suppress the expression of a receptor normally found on the surface of T-cells, making the immune cells less responsive to activation. In contrast, the Nef gene of HIV-1 and a subset of closely related SIVs failed to limit T-cell activation and death.

"Intriguingly, 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 Dr. 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," Dr. 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. Other researchers have reported in the past that rhesus macaques infected with the Nef-deficient virus had extremely low viral loads and limited evidence of disease progression. Similarly, humans infected with Nef-defective HIV progress to disease symptoms slowly, if at all.

While altering HIV's Nef gene may not be a therapeutic possibility for those infected with the virus, these results – along with research conducted by several other teams – suggest the use of treatments that could carefully limit immune system activation in humans. This, Dr. Kirchhoff says, would mimic the tight immune system-virus balance seen in non-human primates.

"A strong immune response can be good in the short term, but if sustained for a long time as in those with HIV, it can exhaust the immune system," Dr, Kirchhoff said. "If you could somehow dampen the response, it might effectively convert the condition to the more chronic, asymptomatic infection seen in monkeys."


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