The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 20 December 2004. doi:10.1084/jem.20041006
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1593-1604
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 675K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Timm, J.
Right arrow Articles by Allen, T. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Timm, J.
Right arrow Articles by Allen, T. M.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
CD8 Epitope Escape and Reversion in Acute HCV Infection

Joerg Timm1, Georg M. Lauer1, Daniel G. Kavanagh1, Isabelle Sheridan3, Arthur Y. Kim1, Michaela Lucas3, Thillagavathie Pillay3, Kei Ouchi1, Laura L. Reyor1, Julian Schulze zur Wiesch1, Rajesh T. Gandhi1, Raymond T. Chung2, Nina Bhardwaj4, Paul Klenerman3, Bruce D. Walker1, and Todd M. Allen1

1 Partners AIDS Research Center and Infectious Disease Division, Howard Hughes Medical Institute
2 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
3 Nuffield Department of Clinical Medicine, Peter Medawar Building, University of Oxford, Oxford OX1 3SY, England, UK
4 New York University School of Medicine, New York, NY 10016

Address correspondence to Todd M. Allen, Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Bldg. 149, 13th St., Rm. 6618 B, Boston, MA 02114. Phone: (617) 726-7846; Fax: (617) 724-8586; email: tallen2{at}partners.org

In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70–80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8–restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon {gamma} enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8–associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.

Key Words: HLA footprint • processing mutation • viral evolution • acute hepatitis C • CD8 escape

J. Timm and G.M. Lauer contributed equally to this work.

Abbreviations used in this paper: HCV, hepatitis C virus; ICS, intracellular cytokine staining; ML, maximum likelihood.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS