Abstract:

Host HLA class I (HLA-I) allele-associated immune responses are major forces driving the evolution of HIV-1 proteins such as Gag and Nef. The viral protein U (Vpu) is an HIV-1 accessory protein responsible for CD4 degradation and enhancement of virion release by antagonizing tetherin/CD317. Although Vpu represents one of the most variable proteins in the HIV-1 proteome, it is still not clear to what extent HLA-I influence its evolution. To examine this issue, we enrolled 240 HLA-I-typed, treatment naïve, chronically HIV-infected subjects in Japan, and analyzed plasma HIV RNA nucleotide sequences of the vpu region. Using a phylogenetically-informed method incorporating corrections for HIV codon covariation and linkage disequilibrium among HLA alleles, we investigated HLA-associated amino acid mutations in the Vpu protein as well as in the translational products encoded by alternative reading frames. Despite substantial amino acid variability in Vpu, we identified only 4 HLA-associations in all possible translational products encoded in this region, suggesting that HLA-associated immune responses had minor effects on Vpu variability in this cohort. Rather, despite its size (81 amino acids), Vpu showed 103 codon-codon covariation associations, suggesting that Vpu conformation and function are preserved through many possible combinations of primary and secondary polymorphisms. Taken together, our study suggests that Vpu has been comparably less influenced by HLA-I-associated immune-driven evolution at the population level compared to other highly variable HIV-1 accessory proteins.

日本語要旨:

熊本大学エイズ学研究センターとの共同研究で、HLA class-I拘束性CTLは、HIVのアクセサリー遺伝子Vpuに対する免疫逃避には関連が強くないことを見いだした。