Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.

Matthias Hoffmann,Helen Brown,Nikos Pantazis,Jacob Hurst,Stephen Hickling,Julie Fox,Jodi Meyerowitz,Abdel Babiker,John Frater,Jonathan Weber,Nneka Nwokolo,Nicola Robinson,Sarah Fidler,Martin Fisher,Rodney E Phillips ,Christian Willberg ,Spartac ,Geneviève Martin ,S Kinloch ,Cherub Investigators

doi:10.1371/journal.ppat.1005661

Abstract

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.

Highlights

Following infection with Human Immunodeficiency Virus Type 1 (HIV-1) the rate at which an individual develops AIDS is highly variable ranging from ‘progressors’ who, if untreated, experience rapid CD4 T cell decline in months to years to ‘elite controllers’, who spontaneously maintain undetectable plasma viraemia, often for decades
We find a complex picture in which these markers alone, together and in combination with other markers that reflect T cell activation (CD38) help predict the speed of clinical progression and immune decline, with differing effects dependent on the duration of infection
In HIV-1 infection T cell exhaustion is associated with the up-regulation of surface molecules called immune checkpoint receptors (ICRs) such as PD-1, Tim-3 and Lag-3 [12,17,18,19,20], which have been associated with the size of the HIV reservoir and time to viral rebound after therapy cessation[21,22]

Summary

Introduction

Following infection with Human Immunodeficiency Virus Type 1 (HIV-1) the rate at which an individual develops AIDS is highly variable ranging from ‘progressors’ who, if untreated, experience rapid CD4 T cell decline in months to years to ‘elite controllers’, who spontaneously maintain undetectable plasma viraemia, often for decades. In HIV-1 infection T cell exhaustion is associated with the up-regulation of surface molecules called immune checkpoint receptors (ICRs) such as PD-1, Tim-3 and Lag-3 [12,17,18,19,20], which have been associated with the size of the HIV reservoir and time to viral rebound after therapy cessation[21,22]. We sought to determine whether, in primary HIV-1 infection (PHI), these indicators of CD8 T cell exhaustion would correlate with surrogate markers of disease (e.g. HIV-1 plasma viral load (pVL), CD4 T cell count) and actual time to progression within a strictly defined patient population enrolled into a randomized clinical trial of early antiretroviral therapy (ART). We found significant associations between ICR expression and both pVL and disease progression, and an enhanced effect when co-expressed on activated T cells

Methods

Results

Discussion

Conclusion