Immune Dysfunctions of CD56(neg) NK Cells Are Associated With HIV-1 Disease Progression

BACKGROUND: Populations of natural killer cells lacking CD56 expression [CD56(neg) natural killer (NK) cells] have been demonstrated to expand during human immunodeficiency virus (HIV)-1 infection. However, their phenotypic and functional characteristics have not been systematically analyzed, and their roles during disease progression remain poorly understood. METHODS: In this study, 84 donors, namely 34 treatment-naïve HIV-1-infected patients (TNs), 29 HIV-1-infected patients with successful antiretroviral therapy (ARTs), and 21 healthy controls (HCs), were enrolled. The phenotypic and functional characteristics of CD56(neg) NK cells were analyzed using single-cell RNA-sequencing (scRNA-seq) and flow cytometry. A potential link between the characteristics of CD56(neg) NK cells and the clinical parameters associated with HIV-1 disease progression was examined. RESULTS: The frequency of the CD56(neg) NK cell population was significantly increased in TNs, which could be partially rescued by ART. Flow cytometry analyses revealed that CD56(neg) NK cells were characterized by high expression of CD39, TIGIT, CD95, and Ki67 compared to CD56(dim) NK cells. In vitro assays revealed reduced IFN-γ and TNF-α secretion, as well as decreased expression of granzyme B and perforin in CD56(neg) NK cells. In line with the data obtained by flow cytometry, scRNA-seq analysis further demonstrated impaired cytotoxic activities of CD56(neg) NK cells. Notably, a negative correlation was observed between CD39, CD95, and Ki67 expression levels in CD56(neg) NK cells and CD4(+) T cell counts. CONCLUSIONS: The results presented in this study indicate that the CD56(neg) NK cell population expanded in HIV-1-infected individuals is dysfunctional and closely correlates with HIV-1 disease progression.