Definition of the Viral Targets of Protective HIV-1-Specific T Cell Responses

Background:The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction ofresponses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccinedesigns are largely based on viral sequence alignments only, not incorporating experimental data on T cellfunction and specificity.Methods:Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a “protective ratio” (PR) wascalculated as the ratio of median viral loads (VL) between OLP non-responders and responders.Results:For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence.There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLPwere of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitroantiviral activities and, importantly, were at least as predictive of individuals’ viral loads than their HLA class Igenotypes.Conclusions:The data thus identify immunogen sequence candidates for HIV and provide an approach for T cellimmunogen design applicable to other viral infections.