PD-1 blockade following ART interruption enhances control of pathogenic SIV in rhesus macaques

Abstract

Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after anti-retrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody ( n = 7) or saline ( n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIV-specific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100- to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research.

Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption.

“…CTLA4) and TLR 7/8 agonists 38,39,66-68 have shown any significant increase in time to viral rebound or any reduction in the magnitude of viral rebound post-ATI. Administration of anti-PD-1 post-ATI in chronically infected, ART treated RMs led to a transient (two weeks) one log decline of viremia in a subset of RMs who have received repeated infusions of the anti-PD-1 antibody 68 . Studies presented in this manuscript provide evidence for specific mechanisms that will enhance the capacity of anti-PD-1 to rescue innate and adaptive immune responses leading to long term control of viral rebound.…”

Chronic viral infection compromises the quality of circulating mucosal-invariant T cells and follicular T helper cells via expression of both activating and inhibitory receptors

“…Virus-speci c T cells express multiple inhibitory receptors during chronic infections eventually impairing T cell functions. Studies in murine [11] simian [12] and humans have shown that blockade of the inhibitory molecules restores immune functions in vitro as well as in vivo [9]. CD4 + T cells provide help to other effector cells, especially CD8 + T cells to aid in their activation and cytokine production (TNF-α and IFN-γ), and contact-dependent cytotoxicity via perforin/granzyme synthesis and/or Fas-FasL interactions to render in viral elimination [13].…”

Immune checkpoint inhibition as a therapeutic strategy for HIV eradication: current insights and future directions

“…Recent preclinical and clinical approaches using ICIs have explored their development as putative LRAs in addition to the enhancement of antiviral immunity. Indeed, while some studies have reported enhanced viral virus-specific CD8 + T-cell function following ICI treatment, including increased expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) [23,33 ▪▪ ,34], other studies have found no changes within virus-specific CD8 + T-cell function [35,36]. Rahman et al [23] recently reported that anti-PD-1 therapy could expand granzyme B + CXCR5 + CD8 + T cells in lymph nodes after ART discontinuation, implying a possible contribution of CXCR5 + TCF-1 + CD8 + T cells, a feature of progenitor or stem-like T-effector cells.…”

“…However, there is ongoing debate over whether specific classes of ICIs function as LRAs. Although most ICIs tested in preclinical NHP models, including anti-PD-1 and anti-CTLA-4, have shown prominent viral reactivation and significant decreases in viral RNA and DNA after treatment, they have ultimately failed to prevent viral rebound or showed only delayed rebound after ART cessation [23,33 ▪▪ ,34,35]. For example, a study by Bekerman et al [36] supported by Gilead reported that single or combination treatment with nivolumab (anti-PD-1) and vesatolimod (TLR7 agonist) achieved immune activation dependent on vesatolimod but failed to prevent or delay viral rebound or induce delayed control of viremia after ART release in SIV-infected rhesus macaques.…”