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.
Abstract 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.