Increased sequence coverage through combined targeting of variant and conserved epitopes correlates with control of HIV replication

J Virol. 2014 Jan;88(2):1354-65. doi: 10.1128/JVI.02361-13. Epub 2013 Nov 13.


A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-γ/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P = 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P = 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r = 0.62, P = 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r = -0.38, P = 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r = 0.50, P = 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cohort Studies
  • Conserved Sequence
  • Epitopes / chemistry
  • Epitopes / genetics
  • Epitopes / immunology*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / classification
  • HIV-1 / genetics
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / virology
  • Viral Load
  • Virus Replication*
  • gag Gene Products, Human Immunodeficiency Virus / chemistry
  • gag Gene Products, Human Immunodeficiency Virus / genetics*
  • gag Gene Products, Human Immunodeficiency Virus / immunology*


  • Epitopes
  • Interleukin-2
  • gag Gene Products, Human Immunodeficiency Virus
  • Interferon-gamma