Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA - Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and Simian immunodeficiency virus

Polymorphisms in CC chemokine receptor 5 (CCR5), the major coreceptor of hu man immunodeficiency virus 1 (HIV-1) and simian immunodeficiency virus (SIV ), have a major influence on HIV-1 transmission and disease progression. Th e effects of these polymorphisms may, in part, account for the differential pathogenesis of HIV-1 (immunosuppression) and SIV (natural resistance) in humans and non-human primates, respectively. Thus, understanding the geneti c basis underlying species-specific responses to HIV-1 and SIV could reveal new anti-HIV-1 therapeutic strategies for humans. To this end, we compared CCR5 structure/evolution and regulation among humans, apes, Old World Monk eys, and New World Monkeys. The evolution of the CCR5 cis-regulatory region versus the open reading frame as well as among different domains of the op en reading frame differed from one another. CCR5 cis-regulatory region sequ ence variation in humans was substantially higher than anticipated. Based o n this variation, CCR5 haplotypes could be organized into seven evolutionar ily distinct human haplogroups (HH) that we designated HHA, -B, -C, -D, -E, -F, and -G. HHA haplotypes were defined as ancestral to all other haplotyp es by comparison to the CCR5 haplotypes of non-human primates. Different hu man and non-human primate CCR5 haplotypes were associated with differential transcriptional regulation, and various polymorphisms resulted in modified DNA-nuclear protein interactions, including altered binding of members of the NF-KB family of transcription factors. We identified novel CCR5 untrans lated mRNA sequences that were conserved in human and non-human primates. I n some primates, mutations at exon-intron boundaries caused loss of express ion of selected CCR5 mRNA isoforms or production of novel mRNA isoforms. Co llectively, these findings suggest that the response to HIV-1 and SN infect ion in primates may have been driven, in part, by evolution of the elements controlling CCR5 transcription and translation.