HLA supertypes contribute in HIV type 1 cytotoxic T lymphocyte epitope clustering in Nef and Gag proteins.

Induction of HIV-1-specific cytotoxic T lymphocyte (CTL) responses largely depends upon the presentation of CTL epitopes to the CD8(+) T cells aided by a large number of different HLA class I alleles. Although several studies showed the clustering pattern of HIV-1 CTL epitopes, the underlying reason for this tendency remains unresolved. Moreover, the hypothesis that the CTL epitope clusters tend to coincide with the conserved and hydrophobic regions of HIV-1 proteins has been challenged in recent times. The present study aims to characterize and compare the HIV-1 CTL epitope clusters in terms of restricting HLA alleles, hydrophobicity, and sequence conservation in a proteome-wide manner by including a large number of experimentally validated CTL epitopes from the HIV Molecular Immunology Database. CTL epitope cluster distribution analysis in a proteome-wide manner revealed that only two HIV-1 proteins, namely Nef and Gag, have significant cluster-forming capacity where their epitope localization coincides with the hydrophobic and conserved regions. Furthermore, analyses of proteasomal cleavage sites and HLA anchoring motif frequencies in the epitope-dense regions highlighted the role of specific HLA supertypes such as HLA B07, HLA B58, HLA A02, and HLA A03 in selecting the hydrophobic and conserved amino acid positions within Nef and Gag proteins to be presented as epitopes. Based on our results, we hypothesize that the cluster-forming tendency of HIV-1 CTL epitopes is not a proteome-wide feature confined to Nef and Gag proteins. Their cluster-forming tendency largely depends on the host HLA alleles that contribute significantly in selecting functionally constrained hydrophobic regions within the HIV-1 proteome.