Abstract
BackgroundHIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations. We hypothesized that human populations in west central Africa may have been exposed to SIV prior to the pandemic, and that previous outbreaks may have selected for genetic resistance to immunodeficiency viruses. To test this hypothesis, we examined the genomes of Biaka Western Pygmies, who historically resided in communities within the geographic range of the central African chimpanzee subspecies (Pan troglodytes troglodytes) that carries strains of SIV ancestral to HIV-1.ResultsSNP genotypes of the Biaka were compared to those of African human populations who historically resided outside the range of P. t. troglodytes, including the Mbuti Eastern Pygmies. Genomic regions showing signatures of selection were compared to the genomic locations of genes reported to be associated with HIV infection or pathogenesis. In the Biaka, a strong signal of selection was detected at CUL5, which codes for a component of the vif-mediated APOBEC3 degradation pathway. A CUL5 allele protective against AIDS progression was fixed in the Biaka. A signal of selection was detected at TRIM5, which codes for an HIV post-entry restriction factor. A protective mis-sense mutation in TRIM5 had the highest frequency in Biaka compared to other African populations, as did a protective allele for APOBEC3G, which codes for an anti-HIV-1 restriction factor. Alleles protective against HIV-1 for APOBEC3H, CXCR6 and HLA-C were at higher frequencies in the Biaka than in the Mbuti. Biaka genomes showed a strong signal of selection at TSG101, an inhibitor of HIV-1 viral budding.ConclusionsWe found protective alleles or evidence for selection in the Biaka at a number of genes associated with HIV-1 infection or progression. Pygmies have also been reported to carry genotypes protective against HIV-1 for the genes CCR5 and CCL3L1. Our hypothesis that HIV-1 may have shaped the genomes of some human populations in West Central Africa appears to merit further investigation.
Highlights
HIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations
We examined 64 genes found by genome wide association studies (GWAS) to be associated with HIV-1 susceptibility, infection, control and viral set-point as well as AIDS progression from 9 studies [8,9,38,41,42,43,44,45], including genes that did not meet our criteria for HGAHs, and list those genes that overlapped with regions under putative selection between the ten pair-wise comparisons in Additional file 1: Table S4
In summary, despite small numbers in some studied populations, we found evidence for signatures of recent selection in the Biaka Western Pygmies in genomic regions including CUL5, TRIM5, and TSG101 all of which have a functional role in HIV restriction; and for old selection in the genomic region containing PARD3B, a gene identified by a GWAS
Summary
HIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations. Hypothesis-based candidate gene studies have been conducted on natural history HIV cohorts established in the 1980s consisting of HIV-infected individuals or individuals at risk of HIV exposure by their inclusion in an HIV risk group [1] This strategy has been highly productive and identified a number of gene variants associated with rate of HIV progression or resistance to infection: the CCR5-Δ32 mutation was shown to block HIV acquisition, and HLA class I genes were shown to be strongly associated with HIV progression and control of viral replication [3,4,5,6]. There was little overlap in genes found across the studies [13], with only three human genes identified by all three knock-down studies, and 40 other genes detected by at least two of the studies [10,11,12]
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