Potential mechanisms of PD-1-directed immunotherapy. Blockade of PD-1 pathway helps to restore T and B cell functions during chronic SIV infection. Type I IFN responses are inhibited in the blood and colorectal tissue compartments of SIV-infected Rhesus macaques following in vivo PD-1 blockade. Reduced type I IFN signaling was associated with enhanced expression of intestinal epithelial tight junction-associated genes and with a profound decrease in plasma LPS levels and associated immune activation, suggesting a possible gut repair and decreased pathogenic microbial translocation from gut into the blood. PD-1 blockade enhanced immunity against gut-resident pathogenic bacteria, control of gut-associated pathogenic opportunistic infections, which enhances survival of SIV-infected non-human primates.