Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses

CD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal v...

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Bibliographic Details
Main Author: Sircar, Piya
Other Authors: Letvin, Norman
Language:en_US
Published: Harvard University 2013
Subjects:
HIV
SIV
Online Access:http://dissertations.umi.com/gsas.harvard:10035
http://nrs.harvard.edu/urn-3:HUL.InstRepos:10345145
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spelling ndltd-harvard.edu-oai-dash.harvard.edu-1-103451452015-08-14T15:41:48ZClonal Analysis of Mucosal SIV-Specific CD8+ T Cell ResponsesSircar, PiyaCD8+ T cellsmucosal tissuesrhesus monkeysvaccinesimmunologyHIVSIVCD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal virus control by a vaccine will likely require clonally diverse CD8+ T cells capable of recognizing mutant viruses. Mucosal tissues play a fundamental role in early HIV/SIV pathogenesis by serving as the site for viral entry, CD4+ T cell depletion, and a reservoir for viral replication. Vaccine strategies that induce effective mucosal immunity will likely be critical for protection against HIV/SIV. We examined the SIV Gag p11C-specific CD8+ T cell responses in peripheral blood, gastrointestinal (GI) mucosal and lung mucosal tissues of rhesus monkeys expressing the MHC class I molecule Mamu-A*01. We first investigated the clonal composition of this cell population during the acute and chronic phases of SIVmac infection. We showed that there is a narrowing of the clonal repertoire from acute to chronic infection and the same clonal populations of virus-specific CD8+ T cells are present in the systemic and mucosal compartments of chronically SIV-infected animals. These data indicated that virus-specific CD8+ T cells establish broadly distributed immune responses. Next, we examined the clonal diversity of systemic and mucosal p11C-specific CD8+ T cells induced by prime-boost vaccination. We found that systemic prime-boost vaccination induced clonally diverse p11C-specific populations in mucosal tissues. There were high levels of clonal sharing between systemic and mucosal compartments soon after vaccination. However, later following vaccination there was decreased clonal sharing between the GI mucosa and the systemic circulation. We showed that this was due to limited trafficking of p11C-specific CD8+ T cells to the GI mucosa following vaccination. Overall, these studies indicate that following SIV infection and systemic vaccination the same p11C-specific clones are present in mucosal and systemic compartments. Moreover, the apparent immune compartmentalization is a consequence of differences in cell trafficking between systemic and mucosal CD8+ T cells. These observations have important implications for the design of HIV vaccines that generate effective mucosal immunity.Letvin, Norman2013-02-26T17:21:07Z2013-02-262011Thesis or DissertationSircar, Piya. 2011. Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses. Doctoral dissertation, Harvard University.http://dissertations.umi.com/gsas.harvard:10035http://nrs.harvard.edu/urn-3:HUL.InstRepos:10345145en_USclosed accessHarvard University
collection NDLTD
language en_US
sources NDLTD
topic CD8+ T cells
mucosal tissues
rhesus monkeys
vaccines
immunology
HIV
SIV
spellingShingle CD8+ T cells
mucosal tissues
rhesus monkeys
vaccines
immunology
HIV
SIV
Sircar, Piya
Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
description CD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal virus control by a vaccine will likely require clonally diverse CD8+ T cells capable of recognizing mutant viruses. Mucosal tissues play a fundamental role in early HIV/SIV pathogenesis by serving as the site for viral entry, CD4+ T cell depletion, and a reservoir for viral replication. Vaccine strategies that induce effective mucosal immunity will likely be critical for protection against HIV/SIV. We examined the SIV Gag p11C-specific CD8+ T cell responses in peripheral blood, gastrointestinal (GI) mucosal and lung mucosal tissues of rhesus monkeys expressing the MHC class I molecule Mamu-A*01. We first investigated the clonal composition of this cell population during the acute and chronic phases of SIVmac infection. We showed that there is a narrowing of the clonal repertoire from acute to chronic infection and the same clonal populations of virus-specific CD8+ T cells are present in the systemic and mucosal compartments of chronically SIV-infected animals. These data indicated that virus-specific CD8+ T cells establish broadly distributed immune responses. Next, we examined the clonal diversity of systemic and mucosal p11C-specific CD8+ T cells induced by prime-boost vaccination. We found that systemic prime-boost vaccination induced clonally diverse p11C-specific populations in mucosal tissues. There were high levels of clonal sharing between systemic and mucosal compartments soon after vaccination. However, later following vaccination there was decreased clonal sharing between the GI mucosa and the systemic circulation. We showed that this was due to limited trafficking of p11C-specific CD8+ T cells to the GI mucosa following vaccination. Overall, these studies indicate that following SIV infection and systemic vaccination the same p11C-specific clones are present in mucosal and systemic compartments. Moreover, the apparent immune compartmentalization is a consequence of differences in cell trafficking between systemic and mucosal CD8+ T cells. These observations have important implications for the design of HIV vaccines that generate effective mucosal immunity.
author2 Letvin, Norman
author_facet Letvin, Norman
Sircar, Piya
author Sircar, Piya
author_sort Sircar, Piya
title Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
title_short Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
title_full Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
title_fullStr Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
title_full_unstemmed Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses
title_sort clonal analysis of mucosal siv-specific cd8+ t cell responses
publisher Harvard University
publishDate 2013
url http://dissertations.umi.com/gsas.harvard:10035
http://nrs.harvard.edu/urn-3:HUL.InstRepos:10345145
work_keys_str_mv AT sircarpiya clonalanalysisofmucosalsivspecificcd8tcellresponses
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