Complex positive selection pressures drive the evolution of HIV-1 with different co-receptor tropisms

HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P<0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross-immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development.