TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection

Glen M Chew,Katherine B Hammond,Alan J Korman,Lishomwa C Ndhlovu,Steven G Deeks,Mario Ostrowski,Scott G Hansen,Brooks I Mitchell,Helen L Wu,Benjamin J Burwitz,Tsuyoshi Fujita,Naoto Ishii,Frederick M Hecht,Mark Maurer,Gabriela M Webb,Jason S Reed,Teri Liegler,Jonah B Sacha,Cecilia Shikuma ,Mohamed Abdel‐Mohsen ,Kiera Clayton

doi:10.1371/journal.ppat.1005349

Abstract

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.

Highlights

During chronic viral infections, high antigenic loads continually stimulate T cells leading to progressive loss of function termed “T cell exhaustion” [1]
The emerging consensus has been that these immune cells are functionally ‘exhausted’ or anergic, and they can recognize HIV-1 specific target cells, they are unable to effectively keep up with rapid and dynamic viral replication in an individual
We show that by blocking the TIGIT and Programmed Death-Ligand 1 (PD-L1) pathway, we can reverse the defects of these viral specific immune cells

Summary

Introduction

High antigenic loads continually stimulate T cells leading to progressive loss of function termed “T cell exhaustion” [1] Throughout this period, T cells increase expression of several inhibitory immune receptors that raise the threshold for activation, resulting in suppressed immune responses. Blockade of the PD-1/PD-L1 axis in vivo demonstrated efficacy in restoring simian immunodeficiency virus (SIV)-specific T cell and humoral immunity, and led to a reduction of SIV viremia and in immune activation. This did not completely control virus, suggesting that additional therapies are needed. Synergistic simultaneous dual blockade has yielded more promising responses suggesting these co-inhibitory molecules are non-redundant [10,19,21,22]

Methods

Results

Discussion

Conclusion