HIV-1’s high virulence might be an accident of evolution

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 the June 16, 2006 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.

"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.

"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," he said. "If you could somehow dampen the response, it might effectively convert the condition to the more chronic, asymptomatic infection seen in monkeys."

Further studies by the team will examine whether SIVs carrying Nef genes artificially made incapable of limiting T cell activation might become more pathogenic in their natural monkey hosts. The group will also examine whether Nef variation among HIV-2 strains might explain differences in the rate of progression to disease in infected humans.

Source: Cell Press  


2 thoughts on “HIV-1’s high virulence might be an accident of evolution

  1. Scientistguy

    There’s a lot of holes in this story. The authors need a high MOI to see an effect on the TCR/CD3 by “good” Nef. Not clear this is relevant in vivo. Cells that are infected get killed by the virus or the immune response if the virus is expressing genes – so does will it matter if CD3 is downmodulated from the surface or not? Would be more compelling an argument if they had uncovered a bystander effect on uninfected cells … limiting their activation might limit viral spread. Also, there are exceptions to the “good” Nef vs. “bad” Nef paradigm being presented … HIV-1 carrying “bad” Nef in humans does very little to chimps, despite the lack of CD3 downmod … and SIVmac239 has a “good” Nef by their model as it downmods CD3 … but rhesus animals get killed by SIVmac239. Seems like this is repackaging of what we already know about Nef (that it is a key pathogenic determinant but instead of deleting the twist is looking at an afunctional form) with the phenotypic correlate of CD3 surface regulation, which is an imperfect correlate for reasons stated above.

  2. Thanks for the indepth analysis Scientistguy. After reading the paper carefully, I agree with your conclusions that there number of questions that needs to be addressed to reach the conclusion that it is all about Nef that makes HIV more pathogenic for humans.

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