부산대학교 도서관

Despite their importance, natural killer (NK) cell responses are frequently dysfunctional during human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, even irrespective of antiretroviral therapies, with poorly understood underlying mechanisms. NK cell surface receptor modulation in lentivirus infection has been extensively studied, but a deeper interrogation of complex cell signaling is mostly absent, largely due to the absence of any comprehensive NK cell signaling assay. To fill this knowledge gap, we developed a novel multiplex signaling analysis to broadly assess NK cell signaling. Using this assay, we elucidated that NK cells exhibit global signaling reduction from CD16 both in people living with HIV-1 (PLWH) and SIV-infected rhesus macaques. Intriguingly, antiretroviral treatment did not fully restore diminished CD16 signaling in NK cells from PLWH. As a putative mechanism, we demonstrated that NK cells increased surface ADAM17 expression via elevated plasma IL-18 levels during HIV-1 infection, which in turn reduced surface CD16 downregulation. We also illustrated that CD16 expression and signaling can be restored by ADAM17 perturbation. In summary, our multiplex NK cell signaling analysis delineated unique NK cell signaling perturbations specific to lentiviral infections, resulting in their dysfunction. Our analysis also provides mechanisms that will inform the restoration of dysregulated NK cell functions, offering potential insights for the development of new NK cell-based immunotherapeutics for HIV-1 disease. Author summary: Natural killer (NK) cells exert critical innate effector responses against human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, but their functions are often dysregulated during chronic lentiviral infection with understudied mechanisms. Specifically, the effect on NK cell signaling linked to this immune dysfunction has not been comprehensively elucidated. To fill the gap in knowledge, we developed a novel multiplex signaling assay for NK cells and applied it to NK cells from people living with HIV-1 (PLWH) or SIV-infected rhesus macaques (RM). We illustrated the signaling activation downstream of CD16, a critical receptor for NK cell function, is systemically downregulated in NK cells in chronic lentiviral infection regardless of antiretroviral treatment, which is mediated by inflammatory responses triggered by HIV-1/SIV infection. Taken together, we demonstrated that global CD16 signaling downregulation in NK cells in HIV-1 and SIV infection using our novel multiplex signaling assay and elucidated the putative mechanism of impaired NK cell activities. These data are beneficial to further advance NK cell-based immunotherapeutics for an HIV-1 cure. [ABSTRACT FROM AUTHOR]