Why Are They Resistant to AIDS?
Since the 1980s, it has been documented that chimpanzees infected with HIV in research studies typically control viral replication and remain asymptomatic. In only a few reported cases have infected chimpanzees developed persistent immune activation, CD4 T-cell loss and opportunistic infections characteristic of AIDS.
Since the 1980s it has been documented that chimpanzees infected with HIV in research studies typically control viral replication and remain asymptomatic. In only a few reported cases have infected chimpanzees developed persistent immune activation, CD4 T-cell loss and opportunistic infections characteristic of AIDS. The reasons for the different outcomes between human and chimpanzee HIV infections have been the subject of much theorizing and even controversy. The discovery that chimpanzees are the source of HIV’s closest antecedent, a virus called SIVcpz, led some scientists to hypothesize that chimpanzees alive today may be the descendants of those animals who were able to control SIVcpz and ward off immunodeficiency sometime in the past when SIVcpz first entered the chimpanzee population. In other words, present-day chimpanzees are the survivors of an AIDS epidemic that killed susceptible SIV-infected animals.
In 2002, a paper published by Natasja de Groot and colleagues offered some inferential evidence for this hypothesis. The paper showed that particular immune response genes are common among chimpanzees while others are rare, indicating that something in the past favored the survival of chimps possessing the now common genes. The genes in question are called class I major histocompatibility (MHC) genes and they make proteins that present fragments of pathogens (called epitopes) to CD8 T cells, essentially acting as an alarm signal that prompts recognition of pathogen-infected cells (once recognized, CD8 T cells can then kill the infected cell). There are many different class I MHC gene variants, which in turn make proteins that vary in the efficiency with which they can bind to, and present, pathogen-derived epitopes. The authors of this paper speculated that the class I MHC genes that make proteins capable of efficient presentation of SIVcpz epitopes were those that had been selected for in the present-day chimpanzee population. This theory would explain why most chimps are able to exert strict immune control over the very similar virus, HIV-1.
In a recent issue of the journal AIDS, a group of researchers led by Ilka Hoof from the Technical University of Denmark presented data that offers new and compelling support for this idea. MHC genes in humans are called Human Leukocyte Antigen (HLA) genes and there is now a vast literature demonstrating that certain class I HLA genes are strongly associated with long-term nonprogression of HIV infection and control of viral replication to less than 50 copies in the absence of any treatment (sometimes called “elite control”). Among the strongest associations are with the HLA genes designated B*57 and B*27, which are significantly and consistently overrepresented in cohorts of long-term nonprogressors and elite controllers. These HLA genes have been shown to be associated with CD8 T-cell responses that are particularly good at recognizing a broad array of HIV epitopes, rendering the CD8 T cells very efficient at targeting HIV-infected cells.
The researchers decided to investigate whether there are similarities between the HLA genes associated with control of HIV in humans and the MHC genes now common among chimpanzees. What they found is that the proteins encoded by the human HLA genes are structurally very similar to those encoded by chimpanzee MHC genes. In both cases, the receptors are capable of presenting a particularly broad range of different epitopes from the Gag protein of SIV and HIV. These data strongly suggest that chimpanzees today are descended from the long-term nonprogressors of a past chimpanzee SIVcpz epidemic, and that the conundrum of chimpanzee resistance to AIDS may finally be solved.
Another implication of the research is that if HIV were to spread uncontrolled through the human population, the HLA genes associated with nonprogression would become more common and, as a result, immunological control of HIV replication would become the norm rather than the exception. Thankfully, however, this harsh Darwinian scenario can be avoided with effective treatment and prevention.
It remains uncertain if the findings can assist efforts to develop an effective HIV vaccine; on the one hand, they add to the evidence that CD8 T cells play a crucial role in controlling viral replication but, on the other, it is unclear if vaccination can increase the efficiency of the CD8 T-cell response in people lacking favorable HLA genes. In terms of vaccine targets, the data echo other recent studies indicating that broad responses to the HIV Gag protein are an important correlate of immune control but, again, the ability to induce broad responses to Gag with a vaccine may be dependent on an individual’s HLA genes. Ongoing efforts to enhance and broaden T-cell responses to HIV vaccines should help resolve these uncertainties.
- Hoof, I, Kesmir, C, Lund, O, Nielsen, M. Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection. AIDS 22;11:1299-1303
- de Groot NG, Otting N, Doxiadis GG, et al. Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees. Proc Natl Acad Sci USA 99;18:11748-53