HIV–opioid interactions in the brain microenvironment drive neuroimmune, synaptic, and chromatin-associated transcriptomic remodeling during neurological impairment: insights from human and murine models

HIV remains a major global health concern, as does the connection between HIV infection and the opioid epidemic. Substance abuse increases the risk of HIV transmission and is linked to treatment non-compliance, rapid disease progression, HAND, and higher mortality rates. In recent years, epigenetic modifications have been linked to the development of opioid addiction and neurodegenerative diseases, but despite new insights, the long-term epigenetic effects of HIV and opioid co-occurrence on the severity, progression, and prognosis of HAND are not yet fully understood. In this study, we explored synaptic, immune, and epigenetic alterations associated with HIV and opioid exposure by integrating analyses from human postmortem brain tissue, peripheral blood mononuclear cells, and an EcoHIV-infected mouse model subjected to chronic morphine treatment. RT-PCR of human frontal cortex revealed differential expression of genes involved in synaptic transmission, innate immune activation, and chromatin regulation. In mice, behavioral assessments were combined with transcriptomic and proteomic approaches, including nanoscale liquid chromatography–tandem mass spectrometry, as well as biochemical assays such as RT-PCR, flow cytometry, ELISA, and Western blotting. Data from EcoHIV-infected, morphine-treated mice demonstrated sex-dependent differences in behavioral outcomes, histone modification profiles, and epigenetic regulator expression, along with disruptions in neuronal signaling and neuroinflammatory pathways. Proteomic analyses further identified widespread changes in histone post-translational modifications and altered expression of chromatin-modifying enzymes, indicating global epigenetic remodeling consistent with an altered chromatin state. Together, these findings suggest that HIV infection and opioid exposure cooperatively alter chromatin organization and transcriptional programs in the brain in a sex-dependent manner, potentially contributing to neuroimmune dysregulation and cognitive impairment.