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Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency

HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8(+) T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8(+) T cells on viral rebound. Here, we studied the impact of C...

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Autores principales: Docken, Steffen S., McCormick, Kevin, Pampena, M. Betina, Samer, Sadia, Lindemuth, Emily, Pinkevych, Mykola, Viox, Elise G., Wu, Yuhuang, Schlub, Timothy E., Cromer, Deborah, Keele, Brandon F., Paiardini, Mirko, Betts, Michael R., Bar, Katharine J., Davenport, Miles P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688670/
https://www.ncbi.nlm.nih.gov/pubmed/38032851
http://dx.doi.org/10.1371/journal.ppat.1011755
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author Docken, Steffen S.
McCormick, Kevin
Pampena, M. Betina
Samer, Sadia
Lindemuth, Emily
Pinkevych, Mykola
Viox, Elise G.
Wu, Yuhuang
Schlub, Timothy E.
Cromer, Deborah
Keele, Brandon F.
Paiardini, Mirko
Betts, Michael R.
Bar, Katharine J.
Davenport, Miles P.
author_facet Docken, Steffen S.
McCormick, Kevin
Pampena, M. Betina
Samer, Sadia
Lindemuth, Emily
Pinkevych, Mykola
Viox, Elise G.
Wu, Yuhuang
Schlub, Timothy E.
Cromer, Deborah
Keele, Brandon F.
Paiardini, Mirko
Betts, Michael R.
Bar, Katharine J.
Davenport, Miles P.
author_sort Docken, Steffen S.
collection PubMed
description HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8(+) T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8(+) T cells on viral rebound. Here, we studied the impact of CD8 immune pressure on post-treatment rebound of barcoded SIVmac293M in 14 Mamu-A*01 positive rhesus macaques that initiated ART on day 14, and subsequently underwent two analytic treatment interruptions (ATIs). Rebound following the first ATI (seven months after ART initiation) was dominated by virus that retained the wild-type sequence at the Mamu-A*01 restricted Tat-SL8 epitope. By the end of the two-month treatment interruption, the replicating virus was predominantly escaped at the Tat-SL8 epitope. Animals reinitiated ART for 3 months prior to a second treatment interruption. Time-to-rebound and viral reactivation rate were significantly slower during the second treatment interruption compared to the first. Tat-SL8 escape mutants dominated early rebound during the second treatment interruption, despite the dominance of wild-type virus in the proviral reservoir. Furthermore, the escape mutations detected early in the second treatment interruption were well predicted by those replicating at the end of the first, indicating that escape mutant virus in the second interruption originated from the latent reservoir as opposed to evolving de novo post rebound. SL8-specific CD8(+) T cell levels in blood prior to the second interruption were marginally, but significantly, higher (median 0.73% vs 0.60%, p = 0.016). CD8(+) T cell depletion approximately 95 days after the second treatment interruption led to the reappearance of wild-type virus. This work suggests that CD8(+) T cells can actively suppress the rebound of wild-type virus, leading to the dominance of escape mutant virus after treatment interruption.
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spelling pubmed-106886702023-12-01 Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency Docken, Steffen S. McCormick, Kevin Pampena, M. Betina Samer, Sadia Lindemuth, Emily Pinkevych, Mykola Viox, Elise G. Wu, Yuhuang Schlub, Timothy E. Cromer, Deborah Keele, Brandon F. Paiardini, Mirko Betts, Michael R. Bar, Katharine J. Davenport, Miles P. PLoS Pathog Research Article HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8(+) T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8(+) T cells on viral rebound. Here, we studied the impact of CD8 immune pressure on post-treatment rebound of barcoded SIVmac293M in 14 Mamu-A*01 positive rhesus macaques that initiated ART on day 14, and subsequently underwent two analytic treatment interruptions (ATIs). Rebound following the first ATI (seven months after ART initiation) was dominated by virus that retained the wild-type sequence at the Mamu-A*01 restricted Tat-SL8 epitope. By the end of the two-month treatment interruption, the replicating virus was predominantly escaped at the Tat-SL8 epitope. Animals reinitiated ART for 3 months prior to a second treatment interruption. Time-to-rebound and viral reactivation rate were significantly slower during the second treatment interruption compared to the first. Tat-SL8 escape mutants dominated early rebound during the second treatment interruption, despite the dominance of wild-type virus in the proviral reservoir. Furthermore, the escape mutations detected early in the second treatment interruption were well predicted by those replicating at the end of the first, indicating that escape mutant virus in the second interruption originated from the latent reservoir as opposed to evolving de novo post rebound. SL8-specific CD8(+) T cell levels in blood prior to the second interruption were marginally, but significantly, higher (median 0.73% vs 0.60%, p = 0.016). CD8(+) T cell depletion approximately 95 days after the second treatment interruption led to the reappearance of wild-type virus. This work suggests that CD8(+) T cells can actively suppress the rebound of wild-type virus, leading to the dominance of escape mutant virus after treatment interruption. Public Library of Science 2023-11-30 /pmc/articles/PMC10688670/ /pubmed/38032851 http://dx.doi.org/10.1371/journal.ppat.1011755 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Docken, Steffen S.
McCormick, Kevin
Pampena, M. Betina
Samer, Sadia
Lindemuth, Emily
Pinkevych, Mykola
Viox, Elise G.
Wu, Yuhuang
Schlub, Timothy E.
Cromer, Deborah
Keele, Brandon F.
Paiardini, Mirko
Betts, Michael R.
Bar, Katharine J.
Davenport, Miles P.
Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title_full Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title_fullStr Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title_full_unstemmed Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title_short Preferential selection of viral escape mutants by CD8(+) T cell ‘sieving’ of SIV reactivation from latency
title_sort preferential selection of viral escape mutants by cd8(+) t cell ‘sieving’ of siv reactivation from latency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688670/
https://www.ncbi.nlm.nih.gov/pubmed/38032851
http://dx.doi.org/10.1371/journal.ppat.1011755
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