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

  • Beatriz Mothe ,
  • Anuska Llano ,
  • Javier Ibarrondo ,
  • Marcus Daniels ,
  • Cristina Miranda ,
  • Jennifer Zamarreno ,
  • Vanessa Bach ,
  • Rosario Zuniga ,
  • Susana Perez-Alvarez ,
  • Chirstoph 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. Brumme ,
  • ,
  • Todd M. Allen ,
  • James I. Mullins ,
  • Guadalupe Gomez ,
  • Philip J. Goulder ,
  • Bruce D. Walker ,
  • Jose M. Gatell ,
  • Bonaventura Clotet ,
  • Better T. Korber ,
  • Jorge Sanchez ,
  • Chirstian Brander

Journal of Translational Medicine | , Vol 9(208)

Publication

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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.