The Natural Killer Cell Interferon-Gamma Response to Bacteria Is Diminished in Untreated HIV-1 Infection and Defects Persist Despite Viral Suppression

Objective: Natural killer (NK) cells are important in innate immune responses to bacterial and viral pathogens. HIV-1 infection is associated with opportunistic bacterial infections and with microbial translocation, but the nature of the NK cell response to bacteria during HIV-1 infection has not been studied extensively. The objective of this study was to compare NK cell responses to bacteria in HIV-1-infected versus that in uninfected individuals. Methods: Multicolor flow cytometry was used to evaluate the ability of blood NK cell subsets (CD56(+)CD16(-), CD56(+)CD16(+), and CD56(-)CD16(+)) from treated, virally suppressed, and untreated viremic subjects with chronic HIV-1 infection and uninfected controls, to secrete interferon gamma (IFN-gamma) in response to the in vitro stimulation of peripheral blood mononuclear cells with heat-killed commensal Escherichia coli or pathogenic Salmonella typhimurium. Results: All 3 NK cell subsets produced IFN-gamma in response to bacteria, but CD56(-)CD16(+) NK cells were least responsive. Untreated HIV-1-infected donors had increased frequencies of CD56(-)CD16(+) NK cells and lower overall frequencies of IFN-gamma-producing NK cells responding to E. coli and S. typhimurium than did NK cells from uninfected donors. These NK cell defects were not fully restored in antiretroviral therapy-treated donors. Monocytes were necessary for NK cells to respond to bacteria, but the HIV-associated defect was intrinsic to NK cells because the addition of normal monocytes did not restore IFN-gamma production in response to bacteria. Conclusions: Functional defects and numeric alterations of NK cell subsets lead to decreased frequencies of bacteria-reactive, IFN-gamma-producing NK cells in HIV-1-infected subjects, even those on antiretroviral therapy.