Plasma Derived Extracellular Vesicles Modulate Monocyte IL-18, IFN-α and IL-10 responses in Adults with HIV-related Cognitive Impairment

Abstract

Abstract Background: HIV-associated neurocognitive dysfunction persists despite suppressive antiretroviral therapy (ART). Extracellular vesicles (EVs) are emerging modulators of immunological responses. We have previously shown that EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment (CI). Whether these EV changes observed in people with HIV (PWH) influence innate cellular function among those with CI remains unclear. Method: Purified EV samples from 58 HIV-infected individuals on ART with either cognitive impairment (CI, n=48) or normal cognition (NC, n=10) and 8 uninfected controls were isolated using differential centrifugation and co-cultured with PBMCs from a single uninfected donor for 18 hrs. Eight intracellular cytokines and 13 surface chemokines and myeloid differentiation markers were assessed by spectral flow cytometry. Non-parametric statistical T tests were used. Result: Monocytes (mono) showed differential effects on multiple cytokine responses and cell surface receptors after exposure to EVs from HIV-infected individuals with or without CI. Levels of mono IL-18 were significantly lower after incubation with EVs derived from HIV-infected individuals compared to uninfected controls. Based on cognitive status, EVs from HIV-CI group significantly lower % of IL-18 mono responses and lower IFN-α and higher IL-10 responses on a per cell basis when compared to the NC group. Conclusion: These results suggest EVs can modulate mono function irrespective of HIV status. PWH with CI exhibited altered EV driven mono cytokine responses. Our data support interventions that target EVs to reverse or restore mono perturbations and limit neuropathology in PWH on ART. Supported by grants from NIH (R21NS106970 and R01NS117458)