Abstract
BackgroundCD8+ T cell responses are often detected at large magnitudes in HIV-infected subjects, and eliciting these responses is the central aim of many HIV-1 vaccine strategies. Population differences in CD8+ T cell epitope specificity will need to be understood if vaccines are to be effective in multiple geographic regions.Methodology/Principal FindingsIn a large Kenyan cohort, we compared responsive CD8+ T cell HIV-1 Env overlapping peptides (OLPs) to Best Defined Epitopes (BDEs), many of which have been defined in clade B infection. While the majority of BDEs (69%) were recognized in this population, nearly half of responsive OLPs (47%) did not contain described epitopes. Recognition frequencies of BDEs were inversely correlated to epitopic sequence differences between clade A1 and BDE (P = 0.019), and positively selected residues were more frequent in “new” OLPs (without BDEs). We assessed the impact of HLA and TAP binding on epitope recognition frequencies, focusing on predicted and actual epitopes in the HLA B7 supertype.Conclusions/SignificanceAlthough many previously described CD8 epitopes were recognized, several novel CD8 epitopes were defined in this population, implying that epitope mapping efforts have not been completely exhausted. Expansion of these studies will be critical to understand population differences in CD8 epitope recognition.
Highlights
The immunodominance of T cell responses, or the relative proportion of the overall response attributable to any one given epitope, is governed by many factors[1]
Given our data that sequence differences can have a negative impact on recognition frequency, these analyses suggest that new epitopes might not have been recognized previously because they lie in regions of human immunodeficiency virus (HIV) that are less evolutionarily constrained and escapable, removing potential epitopes from circulation in a given population
HIV-specific CD8+ T cell responses have been defined primarily in clade B-infected subjects, which account for a small minority of the global HIV-1 pandemic
Summary
The immunodominance of T cell responses, or the relative proportion of the overall response attributable to any one given epitope, is governed by many factors[1]. Successful epitopes must ‘‘pass’’ several steps before generating a response, including proteosomal cleavage, stability in the cytosol, ability to bind Transporter associated protein (TAP) and Human leukocyte antigen (HLA) alleles, and recognition by an appropriate T cell receptor (TCR). For pathogens such as human immunodeficiency virus (HIV), in addition to the above factors, the repertoire of available epitopes may critically differ between different viral strains. A better understanding of factors that influence CD8+ T cell recognition in HIV infection, in the setting of different HIV clades, is of critical importance for HIV-1 vaccine efforts. Population differences in CD8+ T cell epitope specificity will need to be understood if vaccines are to be effective in multiple geographic regions
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