Hiv increases the inhibitory impact of morphine and antiretrovirals on autophagy in primary human macrophages: Contributions to neuropathogenesis

HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15–40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluores-cence in primary human macrophages, we demonstrated that morphine and a commonly pre-scribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of au-tophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mi-tophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing au-tophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.