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Journal of Virology, February 2009, p. 1228-1239, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01545-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HLA-Associated Clinical Progression Correlates with Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection{triangledown}

A. Duda,1,2 L. Lee-Turner,1,2 J. Fox,3 N. Robinson,1,2 S. Dustan,3 S. Kaye,3 H. Fryer,2,4 M. Carrington,5 M. McClure,3 A. R. Mclean,2,4 S. Fidler,3 J. Weber,3 R. E. Phillips,1,2* A. J. Frater,1,2 and the SPARTAC Trial Investigators

Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, Oxford University, South Parks Road, Oxford OX1 3SY, United Kingdom,1 The James Martin 21st Century School at The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom,2 Division of Medicine, Wright Fleming Institute, Imperial College, St. Mary's Hospital, Norfolk Place, Paddington, London W2 1PG, United Kingdom,3 Department of Zoology, Oxford University, South Parks Road, Oxford OX1 3PS, United Kingdom,4 Basic Research Program, SAIC-Frederick, Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland5

Received 22 July 2008/ Accepted 21 October 2008

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.

* Corresponding author. Mailing address: Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom. Phone: 44 01865 281230. Fax: 44 01865 281890. E-mail: rodney.phillips{at}ndm.ox.ac.uk

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1228-1239, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01545-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Brumme, Z. L., Walker, B. D. (2009). Tracking the culprit: HIV-1 evolution and immune selection revealed by single-genome amplification. JEM 206: 1215-1218 [Abstract] [Full Text]  


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