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Published on: December 20, 2024
MicroPET evidence for a hypersensitive neuroinflammatory profile of gp120 mouse model of HIV
Jared W Young1, Christopher V Barback2, Louise A Stolz3
1Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
Abstract:
Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive deficits persist. Determining biological mechanism(s) underlying abnormalities is critical to minimize the long-term impact of HIV. Positron emission tomography (PET) studies reveal that PLWH exhibit elevated neuroinflammation, potentially contributing to these problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV entry into a cell contributing to HIV-related neurotoxicity. In vivo evidence for mice overexpressing gp120 (transgenic) mice exhibiting neuroinflammation remains unclear. Here, we conducted microPET imaging in gp120 transgenic and wildtype mice, using the radiotracer [(18)F]FEPPA (binds to the translocator protein expressed by activated microglial serving as a neuroinflammatory marker). Imaging was performed at baseline and 24 h after lipopolysaccharide (LPS; 5 mg/kg) treatment (endotoxin that triggers an immune response). Gp120 transgenic mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus. Gp120 transgenic mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or sensitive to any treatments.
Insights
HIV-infected individuals show heightened brain inflammation. Gp120 transgenic mice, mimicking HIV
Area of Science:
- Neuroscience
- Immunology
- Radiochemistry
Background:
- People living with HIV (PLWH) often experience persistent cognitive deficits despite increased survival.
- Neuroinflammation, indicated by elevated microglial activation, is a key factor in HIV-associated neurotoxicity.
- The HIV envelope glycoprotein gp120 is implicated in neurotoxicity, but in vivo evidence in animal models is limited.
Purpose of the Study:
- To investigate neuroinflammation in mice genetically engineered to express HIV's gp120 protein.
- To determine if gp120 expression sensitizes the brain to inflammatory stimuli.
- To establish an in vivo model for studying HIV-related neuroinflammation.
Main Methods:
- MicroPET imaging was performed on gp120 transgenic and wildtype mice.
- The radiotracer [(18)F]FEPPA, targeting the translocator protein on activated microglia, was used.
- Mice were imaged at baseline and 24 hours after lipopolysaccharide (LPS) administration to induce inflammation.
Main Results:
- Gp120 transgenic mice showed significantly higher [(18)F]FEPPA uptake compared to wildtype mice post-LPS treatment.
- This elevated neuroinflammation was observed across multiple brain regions, including the striatum, hypothalamus, and hippocampus.
- Gp120 transgenic mice demonstrated hypersensitivity to inflammatory challenges.
Conclusions:
- Mice expressing HIV's gp120 exhibit heightened in vivo neuroinflammation in response to immune activation.
- This gp120 transgenic model recapitulates inflammatory hypersensitivity seen in people living with HIV.
- This model offers a valuable tool for further research into HIV-related neuroinflammation and potential therapeutic interventions.
