Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control

Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T...

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Main Authors: Adland, Emily, Carlson, Jonathan M., Paioni, Paolo, Kløverpris, Henrik, Shapiro, Roger, Ogwu, Anthony, Riddell, Lynn, Luzzi, Graz, Chen, Fabian, Balachandran, Thambiah, Heckerman, David, Stryhn, Anette, Edwards, Anne, Ndung’u, Thumbi, Walker, Bruce D., Buus, Søren, Goulder, Philip, Matthews, Philippa C.
Format: Online
Language:English
Published: Public Library of Science 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759414/
id pubmed-3759414
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spelling pubmed-37594142013-09-10 Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control Adland, Emily Carlson, Jonathan M. Paioni, Paolo Kløverpris, Henrik Shapiro, Roger Ogwu, Anthony Riddell, Lynn Luzzi, Graz Chen, Fabian Balachandran, Thambiah Heckerman, David Stryhn, Anette Edwards, Anne Ndung’u, Thumbi Walker, Bruce D. Buus, Søren Goulder, Philip Matthews, Philippa C. Research Article Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified. Public Library of Science 2013-09-02 /pmc/articles/PMC3759414/ /pubmed/24023819 http://dx.doi.org/10.1371/journal.pone.0073117 Text en © 2013 Adland et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Adland, Emily
Carlson, Jonathan M.
Paioni, Paolo
Kløverpris, Henrik
Shapiro, Roger
Ogwu, Anthony
Riddell, Lynn
Luzzi, Graz
Chen, Fabian
Balachandran, Thambiah
Heckerman, David
Stryhn, Anette
Edwards, Anne
Ndung’u, Thumbi
Walker, Bruce D.
Buus, Søren
Goulder, Philip
Matthews, Philippa C.
spellingShingle Adland, Emily
Carlson, Jonathan M.
Paioni, Paolo
Kløverpris, Henrik
Shapiro, Roger
Ogwu, Anthony
Riddell, Lynn
Luzzi, Graz
Chen, Fabian
Balachandran, Thambiah
Heckerman, David
Stryhn, Anette
Edwards, Anne
Ndung’u, Thumbi
Walker, Bruce D.
Buus, Søren
Goulder, Philip
Matthews, Philippa C.
Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
author_facet Adland, Emily
Carlson, Jonathan M.
Paioni, Paolo
Kløverpris, Henrik
Shapiro, Roger
Ogwu, Anthony
Riddell, Lynn
Luzzi, Graz
Chen, Fabian
Balachandran, Thambiah
Heckerman, David
Stryhn, Anette
Edwards, Anne
Ndung’u, Thumbi
Walker, Bruce D.
Buus, Søren
Goulder, Philip
Matthews, Philippa C.
author_sort Adland, Emily
title Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
title_short Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
title_full Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
title_fullStr Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
title_full_unstemmed Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control
title_sort nef-specific cd8+ t cell responses contribute to hiv-1 immune control
description Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.
publisher Public Library of Science
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759414/
_version_ 1612007587238117376

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