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

• Type of Material: Article
• Authors: Steffen S. Docken, University of New South Wales; Kevin McCormick, University of Pennsylvania; M. Betina Pampena, University of Pennsylvania; Sadia Samer, Emory University; Emily Lindemuth, University of Pennsylvania; Mykola Pinkevych, University of New South Wales; Elise Viox, Emory University; Yuhuang Wu, University of New South Wales; Timothy E. Schlub, University of Sydney; Deborah Cromer, University of New South Wales; Brandon F. Keele, Frederick National Laboratory for Cancer Research; Mirko Paiardini, Emory University; Michael R. Betts, University of Pennsylvania; Katharine J. Bar, University of Pennsylvania; Miles P. Davenport, University of New South Wales
• Language: English
• Date: 2023-11-30
• Publisher: PLoS
• Publication Version: Final Published Version
• Copyright Statement: 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.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): https://doi.org/10.1371/journal.ppat.1011755
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 19
• Issue: 11
• Start Page: e1011755
• Grant/Funding Information: This work was supported in part by NIH grants NIAID P01AI131338 (to MPD, KJB, MRB, and MP); NHLBI, NIDDK, NIMH, NINDS, NIDA, and NIAID 1UM1AI164562-01 (to MP, MPD, and BFK); NIMH R01 MH128155, NIAID P30-AI-045008, R01 AI162646, and UM1AI164570 (to KJB). MPD is supported by an NHMRC Investigator grant (1173027) and an NHMRC Program grant (149990). This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I (BFK). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: viral rebound; treatment interruptions; viral reactivation; antiretroviral therapy; viral immune escape mutations; HIV-specific CD8+ T cells
• Research Categories: Biology, Virology; Biology, Cell

Abstract

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.