Cross-Reactivity to Mutated Viral Immune Targets Can Influence CD8(+) T Cell Functionality: An Alternative Viral Adaptation Strategy

• Type of Material: Article
• Authors: Jennifer Currenti, University of Western Australia; Becker MP Law, University of Western Australia; Kai Qin, University of Alabama Birmingham; Mina John, Murdoch University; Mark A Pilkinton, Vanderbilt University; Anju Bansal, University of Alabama Birmingham; Shay Leary, Murdoch University; Ramesh Ram, Murdoch University; Abha Chopra, Murdoch University; Rama Gangula, Vanderbilt University; Ling Yue, Emory University; Christian Warren, Vanderbilt University; Louise Barnett, Vanderbilt University; Eric Alves, University of Western Australia; Wyatt J McDonnell, Vanderbilt University; Anuradha Sooda, Murdoch University; Sonya L Heath, University of Alabama Birmingham; Simon Mallal, Murdoch University; Paul Goepfert, University of Alabama Birmingham; Spyros A Kalams, Vanderbilt University; Silvana Gaudieri, University of Western Australia
• Language: English
• Date: 2021-10-26
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Currenti, Law, Qin, John, Pilkinton, Bansal, Leary, Ram, Chopra, Gangula, Yue, Warren, Barnett, Alves, McDonnell, Sooda, Heath, Mallal, Goepfert, Kalams and Gaudieri
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.746986
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 746986
• End Page: 746986
• Grant/Funding Information: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was funded by: the National Health and Medical Research Council award number APP1148284 to SG and supports BK; the University of Western Australia award number 000915/12105102 to SG; the Tennessee Center for AIDS Research award number P30 AI110527 to SK; the National Institutes of Health award numbers R01 AI112566 and AI064060 and R56 Al143482 to PG; and the University of Alabama at Birmingham award numbers R24 AI067039 and P30 AI027767 to PG.
• Keywords: Life Sciences & Biomedicine; EXHAUSTION; adaptation; HIV; Immunology; RESPONSES; ACTIVATION; DIVERSITY; NEF; T cell receptor; COMPLEX; RNA-SEQ; ELITE CONTROLLERS; transcriptome; Science & Technology; QUANTITATION; ESCAPE; host-viral interactions
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. Another described, but less understood, adaptation strategy involves the selection of mutations within epitopes that retain immune recognition, suggesting a benefit for the virus despite continued immune pressure (termed non-classical adaptation). To understand this adaptation strategy, we utilized a single cell transcriptomic approach to identify features of the HIV-specific CD8+ T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes containing a non-classical adaptation. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8+ T cells of chronic (n=7) and acute (n=4) HIV-infected subjects identified by either HLA class I tetramers or upregulation of activation markers following peptide stimulation. CD8+ T cells were predominantly dual tetramer+, confirming a large proportion of cross-reactive TCR clonotypes capable of recognizing the NAE and AE form. However, single-reactive CD8+ T cells were identified in acute HIV-infected subjects only, providing the potential for the selection of T cell clones over time. The transcriptomic profile of CD8+ T cells was dependent on the autologous virus: subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an ‘effective’ immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNɣ, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8+ T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.