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

J Transl Med. 2011 Dec 7;9:208. doi: 10.1186/1479-5876-9-208.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Cohort Studies
  • Conserved Sequence / genetics
  • Genetic Heterogeneity
  • HIV Infections / immunology*
  • HIV Infections / virology*
  • HIV-1 / immunology*
  • HIV-1 / physiology
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Male
  • Multivariate Analysis
  • Peptides / immunology
  • Peru
  • Species Specificity
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / virology*
  • Viral Load / immunology
  • Virus Replication / immunology
  • gag Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • Histocompatibility Antigens Class I
  • Peptides
  • gag Gene Products, Human Immunodeficiency Virus