The virulence characteristic of HIV-1 - the virus predominantly responsible for human AIDS - might amount to an accident of evolution, new evidence reveals.
A gene function lost during the course of viral evolution predisposed HIV-1 to spur the fatal immune system failures that are the hallmarks of AIDS, researchers report in Cell.
AIDS has killed more than 25 million people since it was first recognized in 1981, according to The Joint United Nations Programme on HIV and AIDS. In 2005, an estimated 4.1 million were newly infected with the virus. While infection with related strains of "simian immunodeficiency virus" (SIV) is similarly rampant among many species of monkeys, naturally infected nonhuman primates usually don't suffer the symptoms associated with AIDS. The evidence now revealed by an international team of researchers is the first to offer an explanation for this striking difference.
The group found that a viral protein earlier shown 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 viral Nef protein ratchets down the activation of critical agents of immunity called T cells following SIV infection, thereby limiting the detrimental effects otherwise caused by chronically strong immune activation.
The HIV-1 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 full-blown AIDS, reports Frank Kirchhoff of the University of Ulm in Germany and his colleagues.
"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," the researchers 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," 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 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. 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, Kirchhoff noted, functional information about the gene's role had been almost exclusively derived from the HIV-1 version of Nef. To get a broader evolutionary perspective in the current study, Kirchhoff's group examined nef gene variants taken from a variety of divergent SIV lineages.
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, the researchers found. In contrast, they report, 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 Paul Sharp, of the University of Nottingham, who is a leading expert in HIV and SIV evolution.