Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy.

Genevieve E Martin,Nneka Nwokolo,Sarah Fidler,Ane Ogbe,Christian B Willberg,Debattama R Sen,John Frater,John P Thornhill,Julie Fox,W Nicholas Haining,Jodi Meyerowitz,Mathew Jones,Natalia Olejniczak,Nicola Robinson,Emily Adland,Panagiota Zacharopoulou,Lucia Parolini,Matthew Pace,Helen Brown

doi:10.3389/fimmu.2021.647688

Abstract

T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial – but not complete – normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.

Highlights

The natural course of untreated HIV infection is characterised by the development of chronic immune activation and T cell dysfunction
We have characterised the phenotypic and epigenetic features of T cells during primary HIV infection (PHI) and how these are impacted by the initiation of ART early in HIV infection
Primary HIV infection was characterised by major shifts in the differentiation of bulk CD4 and CD8 T cells, in particular by the expansion of activated CD8 T cells with an effector memory (EM) phenotype, which has been well-described in several previous studies [26,27,28, 30]

Summary

Introduction

The natural course of untreated HIV infection is characterised by the development of chronic immune activation and T cell dysfunction. These limit the prospect of immune-mediated viral control, and in particular the inability to clear latentlyinfected CD4 T cells that comprise the HIV reservoir. In the development of HIV cure strategies, individuals who commence therapy early during primary HIV infection (PHI), are of particular interest because a smaller, less genetically diverse HIV reservoir [8,9,10,11,12] may make targeting this pool of latently-infected cells more achievable. Despite early ART initiation, the dynamics of soluble and cellular measures of immune activation are unclear [9, 10, 19,20,21], with potential for persistent damage from the initial immunological insult

Methods

Results

Conclusion