EcoHIV Infection Disrupts Dopamine and Serotonin Transporter Function, Altering Release Dynamics in C57BL/6J Mice.

The long-term expression of neurotoxic viral proteins within the central nervous system plays a critical role in the neuropathology associated with HIV-1, particularly in the development of HIV-1 associated neurocognitive disorders. This hypothesis is predominantly supported by findings from rodent models exposed to the HIV-1 transactivator of transcription (Tat) protein, which exhibit disruptions in monoamine transmission that correlate with cognitive deficits. However, previous studies have often overlooked the complex interactions among other viral proteins. To address this gap, we utilized a novel EcoHIV-infected mouse model designed to elucidate the nuances of monoamine transmission and function. EcoHIV, a chimeric virus with the HIV-1/NL4-3 gp120 coding region replaced by gp80 from ecotropic MuLV-1, facilitates infection in mice and serves as an innovative platform for NeuroHIV research. Results reveal that EcoHIV infection in C57BL/6J mice leads to increased dopamine transporter-mediated dopamine uptake in the prefrontal cortex, while simultaneously reducing serotonin transporter-mediated serotonin uptake in the hippocampus. Fast-scan cyclic voltammetry demonstrated augmented dopamine release in the nucleus accumbens paired with normal release levels in the caudate putamen, contrasted by a significant reduction in serotonin release from the substantia nigra. These alterations were accompanied by heightened horizontal activity in EcoHIV-infected mice. Immunohistochemistry and immunofluorescence analyses further revealed reductions in synaptic density and integrity, alongside microglial activation in the affected brain regions. This research offers crucial insights into the neuropathological progression of HIV-associated neurocognitive and depressive disorders, aligning with clinical evidence observed in people living with HIV and paving the way for potential therapeutic interventions. GRAPHICAL ABSTRACT: One month of EcoHIV infection serves as a model of chronic HIV infection. Chronic exposure to EcoHIV viral proteins via direct interactions with dopamine and serotonin transporters (DAT and SERT) induces neuroadaptations, including neurotransmitter (NT, DA or serotonin) dysregulation and up- or downregulation of DAT and SERT function at synaptic terminals. [Image: see text]