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

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

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.

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