HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection

A. Duda, L. Lee-Turner, J. Fox, N. Robinson, S. Dustan, S. Kaye, H. Fryer, M. Carrington, M. McClure, A. R. Mclean, S. Fidler, J. Weber, R. E. Phillips, A. J. Frater, A. Breckenridge, C. Conlon, D. Cooper, F. Conradie, J. Kaldor, M. SchechterP. Claydon, P. Kaleebu, G. Ramjee, F. Ssali, G. Tambussi

Research output: Contribution to journalArticlepeer-review

Abstract

Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P = 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design.

Original languageEnglish
Pages (from-to)1228-1239
Number of pages12
JournalJournal of Virology
Volume83
Issue number3
DOIs
Publication statusPublished - Feb 2009

ASJC Scopus subject areas

  • Immunology
  • Virology

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