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

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.

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.

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.

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.