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

Jennifer Currenti,Ling Yue,Anuradha Sooda,Abha Chopra,Louise Barnett,Shay Leary,Wyatt J Mcdonnell,Mina John,Sonya L Heath,Silvana Gaudieri,Rama Gangula,Ramesh Ram,Mark A Pilkinton,Spyros A Kalams,Eric Alves,S Mallal ,Christian M Warren ,Betty Yuen‐Kwan Law ,Anju Bansal ,Kai Qin

doi:10.3389/fimmu.2021.746986

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.

Highlights

The rapid mutation rate of human immunodeficiency virus (HIV) remains a central barrier to an effective vaccine, as selection of mutations within the HIV genome by effective antigen-specific CD8+ T cell immune responses causes failure of otherwise potent natural or vaccine-induced immunity
To examine the mechanisms of non-classical adaptation as indicated in Figure 1, CD8+ T cell epitopes within HIV were selected based on prior data from our group that showed adaptation did not reduce T cell recognition of the epitope and subsequent IFNɣ production [14, 15]
Given the differences in human leucocyte antigen (HLA) alleles and the breadth of CD8+ T cell responses between subjects, not all subjects could be tested for the same epitope and only the epitope RF10 could be tested in both the chronic and acute phases of HIV infection

Summary

Introduction

The rapid mutation rate of human immunodeficiency virus (HIV) remains a central barrier to an effective vaccine, as selection of mutations within the HIV genome by effective antigen-specific CD8+ T cell immune responses (termed adaptations) causes failure of otherwise potent natural or vaccine-induced immunity. This form of immune selection pressure is one of the main drivers shaping viral quasispecies during the course of natural infection, highlighting the important role of adaptation in viral pathogenesis [1,2,3]. HIV adaptations are positively selected in infected individuals and are apparent at the population level as human leucocyte antigen (HLA)-specific HIV polymorphisms [4] as the host’s HLA allelic repertoire determine the pathogen-derived peptides (epitopes) that are presented to T cells. Epitopes containing adaptations at non-anchor residue positions continue to be targeted by CD8+ T cells, suggesting alternative non-classical adaptation strategies exploited by HIV [10], and by other mutable pathogens such as hepatitis C virus [11] and others [12, 13], to subvert the host’s immune response

Objectives

Methods

Results

Conclusion