HIV infection of humans and SIV infection of Rhesus macaques generally results in onset of opportunistic infections (OIs) and AIDS when left untreated. In contrast, SIV infection of African monkeys, such as sooty mangabeys, results in high levels of viral replication, but the immune system remains resilient to dysfunction, OIs and progression to AIDS. Here, we set out to identify innate immune correlates associated with acquisition of OIs in HIV+ humans (and the lack thereof in SIV+ mangabeys), through an ex vivo cytokine and transcriptomic assessment of PBMC and monocyte responses to the opportunistic pathogen, BCG. Our data reveal that HIV+ donors have significantly altered NK cell gene expression profiles and deficient monocyte IL-12 production (p=0.017) in response to BCG stimulation compared to HIV-negative donors. In contrast, SIV+ mangabeys maintain similar gene expression profiles and increase the percentage of monocytes producing proinflammatory cytokines TNFα (p=0.03) and IL-12 (p=0.06) following BCG stimulation compared to uninfected mangabeys. These data suggest that a lack of monocyte-derived IL-12 and deficient NK cell response to opportunistic pathogens may be associated with increased susceptibility to OIs. Further, they raise potential to augment innate immune function through NK cell-targeted IL-12 therapy during pathogenic lentiviral infections.