Circulating Platelet-Natural Killer Cell Complexes are Elevated in People Living with HIV on Antiretroviral Therapy

Abstract

Natural killer (NK) cells stand as a critical pillar in the innate immune defense against viral infections, particularly human immunodeficiency virus (HIV). However, during HIV infection, NK cells demonstrate profound dysfunction, undermining effective immune control and accelerating disease progression along with viral persistence. Understanding the mechanisms driving NK cell dysfunction is essential for the development of innovative therapeutic strategies. This study reveals a significant increase in circulating platelet-NK cell complexes (PNKCs) in individuals living with HIV (PWH) on anti-retroviral therapy (ART) compared to those without HIV (PWOH). PWH exhibited distinct NK cell phenotypes within PNKCs, characterized by elevated levels of CD25, IFN-γ, and NKG2D, alongside decreased NKp46, relative to NK cells not engaged in complexes with platelets (non-PNKCs). Moreover, the sustained presence of platelets, or PNKCs, during in vitro NK cell expansion resulted in a heightened population of NK cells exhibiting an activated phenotype. In simian immunodeficiency virus (SIV)-infected Rhesus macaques, PNKC levels were positively correlated with both plasma and cerebrospinal fluid (CSF) viral loads, underscoring the role of PNKCs in disease progression. Notably, this correlation diminished following monoclonal antibody treatment with inclacumab, which inhibits P-selectin-dependent platelet interactions. We propose that the chronic activation of platelets during HIV infection fosters platelet interactions with NK cells in PWH on ART, ultimately contributing to NK cell dysfunction.