Definition of the viral targets of protective HIV-1-specific T cell responses.
Mothe B., Llano A., Ibarrondo J., Daniels M., Miranda C., Zamarreño J., Bach V., Zuniga R., Pérez-Álvarez S., Berger CT., Puertas MC., Martinez-Picado J., Rolland M., Farfan M., Szinger JJ., Hildebrand WH., Yang OO., Sanchez-Merino V., Brumme CJ., Brumme ZL., Heckerman D., Allen TM., Mullins JI., Gómez G., Goulder PJ., Walker BD., Gatell JM., Clotet B., Korber BT., Sanchez J., Brander C.
BACKGROUND: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity. METHODS: Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated 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 OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes. CONCLUSIONS: The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.