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Updated: May 2, 2026
Identification of EcoHIV-Infected Cells in Microglia-Manipulated Transgenic Mice
Published on: December 20, 2024
HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors
Shaona Acharjee1, William G Branton2, Pornpun Vivithanaporn3
1Department of Medicine, University of Alberta, Edmonton, Canada; Department of Physiology and Pharmacology and Hotchkiss Brain Institute, University of Calgary, Bangkok, Thailand.
Background:
Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties.
Methods:
Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection.
Results:
Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p<0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p<0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05).
Conclusions:
HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.
Insights
HIV-1 Nef protein expressed in microglia causes hyperactivity in male mice by disrupting dopamine pathways. This contributes to psychiatric issues seen in HIV/AIDS patients, highlighting viral protein roles in brain disease.
Area of Science:
- Neurovirology
- Neuroimmunology
- Neuropsychiatry
Background:
- Neuropsychiatric disorders are common in HIV/AIDS.
- The specific role of HIV-1 proteins in brain disorders is largely unknown.
- This study investigates the impact of HIV-1 Nef protein in microglia.
Purpose of the Study:
- To examine the neurobehavioral effects of HIV-1 Nef expression in microglia.
- To understand the molecular mechanisms underlying Nef-induced neurobehavioral changes.
- To model HIV-1's contribution to neuropathogenesis.
Main Methods:
- Generated transgenic mice expressing HIV-1 Nef in microglia.
- Assessed neurobehavioral phenotypes using tests like locomotory, forced swim, and elevated plus maze.
- Analyzed gene expression, protein levels, and biogenic amine concentrations.
Main Results:
- Transgenic mice showed Nef expression in microglia and macrophages.
- Male transgenic mice exhibited hyperactivity, including increased locomotion and altered maze exploration.
- Striatal dopamine levels, MAO activity, and DAT expression were reduced in transgenic mice.
- CCL2 expression was increased, and IFN-α was suppressed in the striatum.
Conclusions:
- HIV-1 Nef expression in microglia disrupts striatal dopaminergic transmission.
- This disruption leads to hyperactive behaviors observed in mania and other HIV-associated psychiatric conditions.
- Individual viral proteins play a selective role in the brain's neuropathogenesis.
