The HIV and opioid epidemics intersect, impacting millions of people worldwide. Antiretroviral therapy (ART) has improved and extended the lives of people with HIV, PWH. However, milder chronic HIV associated neurocognitive impairments known as mild HAND or HIV-NCI persist. HIV-NCI affect 15-40% of PWH and because they persist for life, worsen with age, and affect adherence to medications, they can significantly reduce quality of life and increase mortality risk. Many PWH have opioid use disorder, OUD, a comorbidity in PWH that can exacerbate HIV-NCI. Our novel findings in the first funding cycle demonstrate that buprenorphine, a well-established opioid agonist therapy used to treat OUD, may also be a therapy for NCI. Buprenorphine acts as a partial agonist to the mu opioid receptor (MOR) and full antagonist to the kappa opioid receptor (KOR) and according to some studies, it may improve neuropsychological outcomes in people with OUD with or without chronic HIV infection. Our studies suggest that this beneficial activity of buprenorphine may due to its interactions with peripheral blood CD14+CD16+ monocytes, which we showed express MOR and KOR, are preferentially infected with HIV, and have a selective advantage to cross the blood brain barrier (BBB) in response to CCL2 in vitro. This increased transmigration is reduced by buprenorphine, in part by its ability to limit CCL2/CCR2 signaling. Our novel findings in EcoHIV infected mice with HIV-NCI demonstrate that buprenorphine treatment can reverse HIV-NCI in these mice in correlation with a decrease in inflammatory monocytes in their brains, reduction in HIV brain burden, and a reduction in dendritic pruning, a marker of HIV mediated NCI. We hypothesize that buprenorphine mitigates HIV neuropathogenesis and can treat HIV-NCI in PWH with and without OUD. We also propose that this is mediated through its activity on the Mu and Kappa opioid receptors. Our studies will also identify receptor(s) by which buprenorphine is exerting its mechanism of action and will enable the development of second-generation therapies derived from buprenorphine that specifically target these receptor(s). In Aim1, we will characterize in vitro mechanisms of buprenorphine mediated inhibition of CD14+CD16+ monocyte transmigration across the BBB and characterize the role of MOR and KOR in these processes. In Aim 2, we will use genetically modified mice to address individual and combined roles of MOR and KOR in buprenorphine therapy in the preclinical model of EcoHIV driven HIV-NCI and the importance of these receptors specifically on myeloid cells in NCI development. In Aim 3, we will characterize transmigration across a BBB model of mature human monocytes using PBMC from PWH on buprenorphine and correlate this with the PWH's cognitive functions. These will provide further support for use of buprenorphine as a therapy for HIV-NCI in PWH with and without OUD. The studies will be performed by a highly interactive group of HIV scientists, animal model specialists, and infectious diseases, HIV, and OUD physician scientists, and a neuropscychologist, all recognized experts in CNS disease.

The HIV and opioid epidemics intersect, impacting millions of people worldwide. Antiretroviral therapy (ART) has improved and extended the lives of people with HIV, PWH. However, milder chronic HIV associated neurocognitive impairments (NCI) of varying severity known as mild HAND or HIV-NCI persist. HIV-NCI affect 15-40% of PWH and because they persist for life, can worsen with age, and affect adherence to medications, they can significantly reduce quality of life and increase mortality risk. NCI progression appears to correlate with increased HIV in the CNS despite ART. Ongoing low level neuroinflammation also mediates HIV-NCI. Many PWH have opioid use disorder, a comorbidity in PWH that can potentially exacerbate NCI. Our exciting and novel results suggest that buprenorphine, an established opiate substitution therapy (OST) that is used to treat addiction and withdrawal, prevents/reverses cognitive impairment in EcoHIV infected mice, by reducing inflammatory HIV infected/uninfected monocyte entry into the brain, limiting viral seeding of CNS reservoirs, and thus the neuroinflammatory and viral neurotoxic activities that mediate HIV-neurocognitive impairment. Our proposed studies are to characterize the mechanisms by which buprenorphine can mitigate cognitive impairment in PWH with and without OUD. We hypothesize that the positive impact of buprenorphine on HIV- NCI is mediated though MOR and KOR, and specifically their expression on monocytes and myeloid cells. For our innovative studies we will use human monocytes HIV infected in vitro, the Eco-HIV infected mouse model, and PBMC from three different groups of PWH on ART who will undergo cognitive testing at the time of blood draw: 1) PWH taking no opioids or opioid antagonists, 2) PWH taking buprenorphine, and 3) PWH taking prescription opioids.