Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations confer...

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Главные авторы: Draenert, R., Verrill, C. L., Tang, Y., Allen, T. M., Wurcel, A. G., Boczanowski, M., Lechner, A., Kim, A. Y., Suscovich, T., Brown, N. V., Addo, M. M., Walker, B. D.
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Язык:en
Опубликовано: American Society for Microbiology 2004
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Pathogenesis and Immunity
Online-ссылка:https://ncbi.nlm.nih.gov/pmc/articles/PMC368768/
https://ncbi.nlm.nih.gov/pubmed/14694094
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/JVI.78.2.630-641.2004
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spelling pubmed-3687682004-03-17 Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection Draenert, R. Verrill, C. L. Tang, Y. Allen, T. M. Wurcel, A. G. Boczanowski, M. Lechner, A. Kim, A. Y. Suscovich, T. Brown, N. V. Addo, M. M. Walker, B. D. J Virol Pathogenesis and Immunity CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/μl) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques. American Society for Microbiology 2004-01 /pmc/articles/PMC368768/ /pubmed/14694094 http://dx.doi.org/10.1128/JVI.78.2.630-641.2004 Text en Copyright © 2004, American Society for Microbiology
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Pathogenesis and Immunity
spellingShingle Pathogenesis and Immunity
Draenert, R.
Verrill, C. L.
Tang, Y.
Allen, T. M.
Wurcel, A. G.
Boczanowski, M.
Lechner, A.
Kim, A. Y.
Suscovich, T.
Brown, N. V.
Addo, M. M.
Walker, B. D.
Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
description CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/μl) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.
author Draenert, R.
Verrill, C. L.
Tang, Y.
Allen, T. M.
Wurcel, A. G.
Boczanowski, M.
Lechner, A.
Kim, A. Y.
Suscovich, T.
Brown, N. V.
Addo, M. M.
Walker, B. D.
author_facet Draenert, R.
Verrill, C. L.
Tang, Y.
Allen, T. M.
Wurcel, A. G.
Boczanowski, M.
Lechner, A.
Kim, A. Y.
Suscovich, T.
Brown, N. V.
Addo, M. M.
Walker, B. D.
author_sort Draenert, R.
title Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
title_short Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
title_full Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
title_fullStr Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
title_full_unstemmed Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection
title_sort persistent recognition of autologous virus by high-avidity cd8 t cells in chronic, progressive human immunodeficiency virus type 1 infection
publisher American Society for Microbiology
publisher_facet American Society for Microbiology
publishDate 2004
url https://ncbi.nlm.nih.gov/pmc/articles/PMC368768/
https://ncbi.nlm.nih.gov/pubmed/14694094
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/JVI.78.2.630-641.2004
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