Restoring CD8+ T cell anti-HIV activity using combinatorial immune checkpoint blockade

Abstract

Abstract Antiretroviral therapy (ART) effectively reduces viral load and improves life expectancy but does not fully restore host immune function. During chronic infection, T cells upregulate multiple inhibitory immune checkpoint receptors (ICR) which results in the loss of T cell functionality; a state called T cell exhaustion. In this study, we utilized HIV-1 controllers (HC) who have an inherent ability to control viral replication in the absence of ART but eventually gain viral susceptibility due to unknown mechanisms. We hypothesize that efficient control of viral replication becomes compromised by CD8+ T cell exhaustion. Using our cohort, we demonstrate that CD8+ T cells of ART naïve HCs are both necessary and sufficient to suppress viral replication. We also demonstrate that during times of clinical viral control, ART naïve HCs have low expression of exhaustion markers and sustain in vitro viral control. Upon loss of control, our HCs upregulate exhaustion markers and are susceptible to in vitro infection. This study evaluates the synergistic effects of immune checkpoint blockade (ICB) to determine if blockade of ICRs can restore anti-viral functionality of exhausted CD8+ T cells. Using our in vitro spreading infection assay, we demonstrate that treatment with single ICB results in a modest improvement of anti-viral functionality in CD8+ T cells from HCs who have lost viral control. However, former HCs who support in vitro viral replication demonstrate restored suppression of viral replication in tissue culture in the presence of combinatorial anti-PD1 and anti-TIM3 ICB. Our data suggests that combinatorial ICB can restore CD8+ T cells anti-viral functionality and has the potential to be a novel HIV therapeutic intervention.