Evidence for selection at HIV host susceptibility genes in a West Central African human population

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.

CXCR6 gene characterization in two ethnically distinct South African populations and association with viraemic disease control in HIV-1-infected black South African individuals

“…The East sub-Saharan African Luhya population from Kenya however was more similar to the black South African population and also differed markedly from the Yoruba population (data not shown). In a study testing the hypothesis that exposure to simian immunodeficiency virus (SIV) may have led to genetic selection for alleles conferring resistance to immunodeficiency viruses within populations living in SIV endemic regions, the CXCR6 E3K mutation was among the postulated HIV-1 protective alleles found to occur at significantly higher frequencies in Biaka Western Pygmies compared to Mbuti Eastern Pygmies [21]. The former population group historically resided in communities in the same geographical region as the central African chimpanzee ( Pan troglodytes troglodytes ), natural hosts for the SIV strains from which HIV-1 is believed to have originated [21].…”

“…In a study testing the hypothesis that exposure to simian immunodeficiency virus (SIV) may have led to genetic selection for alleles conferring resistance to immunodeficiency viruses within populations living in SIV endemic regions, the CXCR6 E3K mutation was among the postulated HIV-1 protective alleles found to occur at significantly higher frequencies in Biaka Western Pygmies compared to Mbuti Eastern Pygmies [21]. The former population group historically resided in communities in the same geographical region as the central African chimpanzee ( Pan troglodytes troglodytes ), natural hosts for the SIV strains from which HIV-1 is believed to have originated [21]. Interestingly, we found the frequency of the E3K mutation to be higher in black South Africans (48.3%) than in both the Biaka (38%) and Mbuti (12%) as well as the Luhya (41.9%), however the Yoruba population had the highest prevalence of both the E3K (60%) and the rs2234358 3 UTR (76%) mutations.…”

Stabilized Human TRIM5α Protects Human T Cells From HIV-1 Infection

“…[15][16][17] Nonetheless, cohort studies indicate that selected huTRIM5α alleles are associated with altered HIV-1 disease progression, [18][19][20][21] suggesting that huTRIM5α does play a role in ameliorating HIV-1 pathogenesis. Importantly, selected mutations within huTRIM5α that mirror rhTRIM5α dramatically augment restriction activity, with only a single substitution (R332P) required within the B30.2/SPRY domain to confer measureable restriction activity in single-round assays, 22 and as few as five substitutions within the B30.2/SPRY domain conferring potent restriction activity approaching that of rhTRIM5α.…”

Transmission, Evolution, and Endogenization: Lessons Learned from Recent Retroviral Invasions

“…HIV-1 group P likely originates from SIVgor (174). Cross-species transmissions of lentiviruses between nonhuman primates and humans have likely occurred for millennia without reaching epidemic/pandemic scales until modern times (175). The current evidence suggests that this is not due to a change in the rate of interspecies transmission but has more to do with sociodemographic changes, such as massive-scale urbanization in Africa, an increased reliance on bushmeat, and increasing global travel, all of which are highly conducive to the spread of infectious agents (153,176,177).…”