BCG vaccination recalibrates innate immunity in ART-treated people with HIV

Despite suppressive antiretroviral therapy, many people with HIV (PWH) retain chronic interferon-associated immune dysregulation. Observational data from the Swiss HIV Cohort Study linked asymptomatic mycobacterial exposure to lower viral set points, reduced interferon-associated activity, and attenuated HIV-specific antibody responses, a pattern sharing features with HIV elite controllers and natural hosts of primate lentiviruses. We therefore examined whether Bacillus Calmette-Guerin (BCG) vaccination could induce a related immune configuration in ART-treated PWH. Using longitudinal systems-level profiling within the BELIEVE trial, we found that BCG reduced constitutive NK cell IFN-{gamma} production and PBMC-mediated direct cytotoxicity without impairing inducible cytokine responses or antibody-dependent cellular cytotoxicity. Multiomic and proteomic analyses showed reduced interferon- and activation-associated programs, while adaptive immune parameters remained largely stable and follow-up revealed no obvious adverse clinical pattern. This configuration, reduced baseline interferon activity coexisting with preserved Fc-dependent effector function, shares selected features with immune states described in natural lentiviral control and provides a rationale for testing BCG in combination with antibody-based HIV interventions.