Over-activation and dysfunction of platelet-NK cell aggregates in HIV-infected individuals.

BACKGROUND

Human immunodeficiency virus type 1 (HIV-1) infection is associated with over-activation, which contributes to disease progression. Platelet-leukocyte aggregates play a critical role in HIV-1 infection. However, research on the characteristics of platelet-natural killer (NK) cell aggregates in HIV-infected individuals still has certain limitations.

METHODS

Platelet-NK cell aggregates in the peripheral blood of participants were detected by flow cytometry and confirmed by imaging flow cytometry. Platelet activation was evaluated by CD62P expression. The expression of various activating and inhibitory receptors, markers of apoptosis, lipid droplets, interferon-gamma (IFN-γ), Granzyme B, and Perforin in platelet-NK cell aggregates were assessed. The signaling lymphocyte activating molecule (SLAM) family receptors in both platelets and NK cells and the levels of phosphorylation signals in NK cells were respectively measured through flow cytometry.

RESULTS

In this study, we observed an increase in platelet-NK cell aggregates that were negatively correlated with CD4 count, a prognostic marker for HIV-1 disease progression. Furthermore, platelet activation was inversely associated with both HIV-1 disease progression and the platelet-NK cell aggregates. However, antiretroviral therapy (ART) couldn't restore the levels of these aggregates or platelet activation. Compared to platelet-free NK cells, platelet-NK cell aggregates exhibited over-activation (CD69) and exhaustion phenotypes (CD39, LAG-3, PD-1), increased levels of apoptosis (Annexin V and CD95) and lipid droplets (Bodipy 493/503 and LipidTOX). Furthermore, NK cells' cytokine secretion (IFN-γ) and cytotoxic function (Granzyme B and Perforin) within the aggregates were declined. Screening results of SLAM receptors in NK cells and platelets suggested that platelets may transmit signals to NK cells via SLAMF5. Moreover, elevated levels of p-Fyn, p-PLC-γ2, p-SHP-1, and p-SHP-2 denoted disturbances in the downstream signals of the SLAM family within platelet-NK cell aggregates.

CONCLUSION

Our study indicates that platelet-NK cell aggregates exhibit characteristics of over-activation and dysfunction during HIV-1 infection. Hyperactivated platelets and the formation of platelet-NK cell aggregates contribute to the HIV-1 disease progression and the inflammation of the immune system. These findings may implicate potential targets of overactivated platelets for HIV-1 disease progression.