Critical effect of Pol escape mutations associated with detrimental allele HLA-C(∗)15:05 on clinical outcome in HIV-1 subtype A/E infection

The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has been investigated in very few studies. HLA-A∗29:01-B∗07:05-C∗15:05 is a detrimental haplotype in HIV-1 subtype A/E-infected Vietnamese individuals. The accumulation of mutations at Pol 653/657 is associated with a poor clinical outcome in these individuals. However, the detrimental HLA allele and the mechanism responsible for its detrimental effect remains unknown. Therefore, in this current study we identified the detrimental HLA allele and investigated the mechanism responsible for the detrimental effect. DESIGN AND METHODS: A T-cell epitope including Pol 653/657 and its HLA restriction were identified by using overlapping HIV-1 peptides and cell lines expressing a single HLA. The effect of the mutations on the T-cell recognition of HIV-1-infected cells was investigated by using target cells infected with the mutant viruses. The effect of these mutations on the clinical outcome was analyzed in 74 HLA-C∗15:05(+) Vietnamese infected with the subtype A/E virus. RESULTS: We identified HLA-C∗15:05-restricted SL9 epitope including Pol 653/657. PolS653A/T/L mutations within this epitope critically impaired the T-cell recognition of HIV-1-infected cells, indicating that these mutations had escaped from the T cells. T-cell responders infected with these mutants showed significantly lower CD4(+) T-cell counts than those with the wild-type virus or Pol S653K/Q mutants, which are not associated with HLA-C∗15:05. CONCLUSION: The accumulation of Pol S653A/T/L escape mutants critically affected the control of HIV-1 by SL9-specific T cells and led to a poor clinical outcome in the subtype A/E-infected individuals having the detrimental HLA-C∗15:05 allele.