Definition of the viral targets of protective HIV-1-specific T cell responses

Beatriz Mothe, Anuska Llano, Javier Ibarrondo, Marcus Daniels, Cristina Miranda, Jennifer Zamarreño, Vanessa Bach, Rosario Zuniga, Susana Pérez-Álvarez, Christoph T. Berger, Maria C. Puertas, Javier Martinez-Picado, Morgane Rolland, Marilu Farfan, James J. Szinger, William H. Hildebrand, Otto O. Yang, Victor Sanchez-Merino, Chanson J. Brumme, Zabrina L. BrummeDavid Heckerman, Todd M. Allen, James I. Mullins, Guadalupe Gómez, Philip J. Goulder, Bruce D. Walker, Jose M. Gatell, Bonaventura Clotet, Bette T. Korber, Jorge Sanchez, Christian Brander

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114 Citations (Scopus)

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. © 2011 Mothe et al; licensee BioMed Central Ltd.
Original languageEnglish
Article number208
JournalJournal of Translational Medicine
Volume9
Issue number1
DOIs
Publication statusPublished - 7 Dec 2011

Keywords

  • Clade B
  • Clade C
  • Entropy
  • Epitope
  • Functional avidity
  • HIV specific CTL
  • HLA
  • Immune correlate
  • Vaccine immunogen design

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