TIGIT Blockade: A Multipronged Approach to Target the HIV Reservoir.

Kayla A Holder,Michael D Grant

doi:10.3389/fcimb.2020.00175

Abstract

During chronic human immunodeficiency virus type 1 (HIV-1) infection, upregulation of inhibitory molecules contributes to effector cell dysfunction and exhaustion. This, in combination with the ability of HIV-1 to reside dormant in cellular reservoirs and escape immune recognition, makes the pathway to HIV-1 cure particularly challenging. An idealized strategy to achieve HIV-1 cure proposes combined viral and immune activation by “shock”ing HIV-1 out of latency and into an immunologically visible state to be recognized and “kill”ed by immune effector cells. Here we outline the potential for blockade of the inhibitory immune checkpoint T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) to overcome natural killer (NK) cell and T cell inhibition associated with HIV-1 infection and invigorate antiviral effector cell responses against HIV-1 reactivated from the latent cellular reservoir.

Highlights

Combination antiretroviral therapy reduces human immunodeficiency virus type 1 (HIV-1) replication to levels where the amount of viral ribonucleic acid (RNA) in the bloodstream falls below current limits of detection
Various types of cells including macrophages, monocytes and astrocytes can serve as HIV-1 reservoirs, the predominant cell type containing HIV-1 provirus are CD4+ T cells and, they are the predominant source of viral replication with withdrawal of Combination antiretroviral therapy (cART) (Finzi et al, 1999; Wong et al, 2019)
We focused this review on the T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) immune checkpoint receptor as expression of TIGIT, its competitors, and its ligands are broadly dysregulated on multiple cell types in HIV-1 infection

Summary

INTRODUCTION

Combination antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication to levels where the amount of viral ribonucleic acid (RNA) in the bloodstream falls below current limits of detection. One hallmark of chronic HIV-1 infection is disruption of normal lymphocyte functions, leading to signs and symptoms of immune exhaustion This exhaustion profile is illustrated by increased expression of multiple inhibitory immune checkpoint molecules including PD-1, CTLA-4, TIM-3, and LAG-3 on CD8+ T cells and in some instances, on NK cells (Wherry et al, 2007; Anderson et al, 2016). Its widespread expression on NK cells and CD8+ T cells enhances the likelihood of TIGIT blockade having a meaningful impact in the setting of chronic infection In this setting, CD8+ T cells acquire expression of inhibitory receptors, including TIGIT, all contributing to maintenance of an immune exhausted state. Expression of TIGIT on CD8+ T cells and NK cells suggests that TIGIT-specific mAb therapy could synergistically unleash both types of antiviral effector cells to more robustly target active HIV-1 infection

A Ligand for TIGIT Is Enriched on HIV-1 Reservoir Cells

Findings

CONCLUSION