Enhancing immune responses to limit chronic immune activation during SIV

Abstract

The persistent immune activation that is typical of HIV-1 and SIV infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death-1 (PD-1). Targeting this exhaustion pathway could result in improved antiviral immune responses, but there have been concerns that it would also lead to increased inflammation and immunopathology. In this issue of the JCI, Dyavar Shetty et al. demonstrate that blocking PD-1 actually reduced proinflammatory responses and improved immunity in the gut of SIV-infected rhesus macaques, suggesting that this might have therapeutic potential to prevent opportunistic infections in HIV-infected patients.

Figure 1. Simplified model of intestinal immunopathology and restoration with anti–PD-1 antibody treatment in SIV infection.

(A) SIV infection results in a chronic proinflammatory environment, leading to exhausted/dysfunctional T and B cells, increased epithelial turnover, multifocal epithelial breaches and loss, microbial translocation, dramatically elevated ISGs, and macrophage dysfunction including inadequate microbial constituent clearance. (B) Treatment of SIV-infected RMs with anti–PD-1 antibody results in a reduced proinflammatory environment, significantly increased SIV-specific and microbial T and B cell function, increased epithelial barrier maintenance and function with increased tight junction expression, reduced microbial translocation, reduced ISG expression, and potentially restored macrophage function including improved microbial constituent clearance. However, the mechanisms that underlie the effects of anti–PD-1 antibody action are incompletely understood.