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Pyrosequencing Reveals Restricted Patterns of CD8+ T Cell Escape-Associated Compensatory Mutations in Simian Immunodeficiency Virus

CD8+ T cells play a major role in the containment of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. CD8+ T cell-driven variations in conserved regions under functional constraints result in diminished viral replicative capacity. While compensatory mutations o... Full description

Journal Title: Journal of Virology 2011, Vol. 85(24), p.13088
Main Author: Burwitz, Benjamin J.
Other Authors: Sacha, Jonah B. , Reed, Jason S. , Newman, Laura P. , Norante, Francesca A. , Bimber, Benjamin N. , Wilson, Nancy A. , Watkins, David I. , O'Connor, David H
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1098-5514 ; PMID: 21994463
Link: http://jvi.asm.org/content/85/24/13088.full
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recordid: asm21994463
title: Pyrosequencing Reveals Restricted Patterns of CD8+ T Cell Escape-Associated Compensatory Mutations in Simian Immunodeficiency Virus
format: Article
creator:
  • Burwitz, Benjamin J.
  • Sacha, Jonah B.
  • Reed, Jason S.
  • Newman, Laura P.
  • Norante, Francesca A.
  • Bimber, Benjamin N.
  • Wilson, Nancy A.
  • Watkins, David I.
  • O'Connor, David H
subjects:
  • Immune Evasion
  • Mutation, Missense
  • Cd8-Positive T-Lymphocytes -- Immunology
  • Simian Immunodeficiency Virus -- Genetics
ispartof: Journal of Virology, 2011, Vol. 85(24), p.13088
description: CD8+ T cells play a major role in the containment of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. CD8+ T cell-driven variations in conserved regions under functional constraints result in diminished viral replicative capacity. While compensatory mutations outside an epitope can restore replicative capacity, the kinetics with which they arise remains unknown. Additionally, certain patterns of linked mutations associated with CD8+ T cell epitope escape in these highly conserved regions may lead to variable levels of viral fitness. Here, we used pyrosequencing to investigate the kinetics and patterns of mutations surrounding the Mamu-A1*00101-bound Gag(181-189)CM9 CD8+ T cell epitope. We obtained more than 400 reads for each sequencing time point, allowing us to confidently detect the emergence of viral variants bearing escape mutations with frequencies as low as 1% of the circulating virus. With this level of detail, we demonstrate that compensatory mutations generally arise concomitantly with Gag(181-189)CM9 escape mutations. We observed distinct patterns of linked flanking mutations, most of which were found downstream of Gag(181-189)CM9. Our data indicate that, whereas Gag(181-189)CM9 escape is much more complex that previously appreciated, it occurs in a coordinated fashion, with very specific patterns of flanking mutations required for immune evasion. This is the first detailed report of the ontogeny of compensatory mutations that allow CD8+ T cell epitope escape in infected individuals.
language: eng
source:
identifier: ISSN: 1098-5514 ; PMID: 21994463
fulltext: fulltext
issn:
  • 1098-5514
  • 10985514
url: Link


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titlePyrosequencing Reveals Restricted Patterns of CD8+ T Cell Escape-Associated Compensatory Mutations in Simian Immunodeficiency Virus
creatorBurwitz, Benjamin J. ; Sacha, Jonah B. ; Reed, Jason S. ; Newman, Laura P. ; Norante, Francesca A. ; Bimber, Benjamin N. ; Wilson, Nancy A. ; Watkins, David I. ; O'Connor, David H
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subjectImmune Evasion ; Mutation, Missense ; Cd8-Positive T-Lymphocytes -- Immunology ; Simian Immunodeficiency Virus -- Genetics;
descriptionCD8+ T cells play a major role in the containment of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. CD8+ T cell-driven variations in conserved regions under functional constraints result in diminished viral replicative capacity. While compensatory mutations outside an epitope can restore replicative capacity, the kinetics with which they arise remains unknown. Additionally, certain patterns of linked mutations associated with CD8+ T cell epitope escape in these highly conserved regions may lead to variable levels of viral fitness. Here, we used pyrosequencing to investigate the kinetics and patterns of mutations surrounding the Mamu-A1*00101-bound Gag(181-189)CM9 CD8+ T cell epitope. We obtained more than 400 reads for each sequencing time point, allowing us to confidently detect the emergence of viral variants bearing escape mutations with frequencies as low as 1% of the circulating virus. With this level of detail, we demonstrate that compensatory mutations generally arise concomitantly with Gag(181-189)CM9 escape mutations. We observed distinct patterns of linked flanking mutations, most of which were found downstream of Gag(181-189)CM9. Our data indicate that, whereas Gag(181-189)CM9 escape is much more complex that previously appreciated, it occurs in a coordinated fashion, with very specific patterns of flanking mutations required for immune evasion. This is the first detailed report of the ontogeny of compensatory mutations that allow CD8+ T cell epitope escape in infected individuals.
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