Sigma-1 receptor regulates HIV-1 and methamphetamine-induced endothelial/pericyte barrier impairment via strain-specific inflammatory responses and mitochondrial dysregulation.

BACKGROUND: Methamphetamine (METH) use disorder (MUD) is a frequent comorbidity among people with HIV-1 (PWH). While both METH and HIV-1 independently disrupt the brain microvascular system and promote neuroinflammation, the molecular mechanisms underlying their synergistic neurotoxicity remain unclear. The sigma-1 receptor (Sigma-1R) signaling pathway has been suggested as a potential target in METH misuse; however, its involvement in the impact of METH and/or HIV-1 infection on brain pericytes remains unknown. METHODS: Transwell co-cultures of human brain microvascular endothelial cells (HBMECs) and human brain vascular pericytes (HBVPs) were employed to assess the impact of combined METH exposure and infection with HIV-1 on barrier integrity. Moreover, mitochondrial functions, inflammatory mediators, oxidative stress markers, and the expression of interferon-stimulated genes were analyzed. RESULTS: HBVP infection with the CXCR4-tropic HIV-1 strain NL4-3, but not the CCR5-tropic JR-CSF strain, disrupted endothelial/pericyte barrier permeability, reduced transendothelial electrical resistance (TEER), and lowered claudin-5 expression, effects alleviated by pretreatment with Sigma-1R antagonist S1RA (10 µM). S1RA suppressed interleukin-6 (IL-6) release without affecting increased ROS levels and mitigated HIV-1 NL4-3 and METH co-induced proton leak and mitochondrial network fragmentation in a DRP1 phosphorylation-dependent manner. Importantly, METH enhanced replication of HIV-1 NL4-3, a process modulated by the CXCR4/CCL2 signaling pathway rather than Sigma-1R. CONCLUSIONS: The obtained results identify Sigma-1R antagonism as a potential therapeutic strategy to protect microvascular integrity in the context of HIV-1 infection and METH misuse. In addition, they reveal distinct mechanisms that may underly microvascular dysfunction in PWH who experience MUD.