A selective sweep in chimpanzees : is SIV the culprit?

Abstract

The human immunodeficiency virus type 1 (HIV-1) is a major threat to mankind, as most infected individuals develop a lethal disease called acquired immunodeficiency syndrome (AIDS). However, a minority group of individuals are long-term non-progressors (LTNP), and resistance to AIDS is strongly associated with particular major histocompatibility complex (MHC) class I molecules, HLA-B*27/B*57. Chimpanzees, humans closest living relative, are susceptible to HIV-1 infection, but most animals do not contract AIDS. Chimpanzees can be naturally infected with chimpanzee simian immunodeficiency virus (SIVcpz), which is considered to be the initiator of the HIV-1 pandemic. This thesis starts with the characterization of the MHC class I genes of a pedigreed West-African chimpanzee colony, and shows that they have a reduced Mhc class I A repertoire, with only one of six human lineages present. This suggests some kind of natural selection event may have occured. To confirm this, the potential influence of selection operating on the Mhc class I genes was studied by comparing the intron variation between a well-defined human and the West-African chimpanzee population. The analysis revealed that chimpanzees experienced an ancient selective sweep that was most prominent for the Patr-B locus. To examine whether the selective sweep affected other genes located in the MHC region, the major histocompatibility complex class I chain related gene (MIC) was investigated. Humans have MICA and B genes that produce functional transcripts, and display high levels of polymorphism. In chimpanzees we observed that all haplotypes sampled possess a Patr-MICA/B fusion gene, which controls only one lineage showing moderate allelic variation. In addition, limited allelic variation was observed for the different Mhc class II loci. These observations are compatible with a selective sweep targeting the MHC region. Subsequently, comparative genomics, using microsatellite markers pinpointed the selective sweep to the MHC class I region. MHC class I molecules play a central role in the immune defense against intracellular infections; for example viral infections. Aforementioned leaded to the hypothesis that the selective sweep in chimpanzees was presumably caused by HIV-1/SIVcpz or a related ancestral retrovirus, and that the contemporary chimpanzee populations represent the off-spring of AIDS-resistant animals, the survivors of a HIV-1-like pandemic that took place in the distant past. To investigate the hypothesis at the functional level, and whether it relates to AIDS-resistance as observed in HLA-B*27/B*57-positive human LTNP, different Patr-A and -B molecules were studied for their ability to present conserved HIV-1/SIVcpz Gag peptides. The four selected Patr molecules were, like the AIDS-protective HLA-B*27/B*57, found to bind peptides derived from conserved areas of the HIV-1/SIVcpz Gag-protein. Moreover, 94% of the chimpanzees studied possessed at least one Patr class I molecule that can bind peptides from such conserved areas of HIV-1/SIVcpz. In addition, many chimpanzees appear to express several molecules able to bind multiple peptides derived from various conserved Gag regions, suggesting that chimpanzees have developed a “double-lock” strategy to respond to an HIV-1/SIVcpz infection.