Abstract
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.
Highlights
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy
Spatial memory was assessed by the percentage of the time spent in the target quadrant (Time at target quadrant %), path length travelled to the target quadrant (Distance to target quadrant), the percentage of time spent at the platform (Time at platform %), path length travelled to the platform (Distance to platform), the number of platform entries (Platform entries), and latency to platform
We aimed to determine the relationship between long-term HIV Tat expression and neurobehavioral, pathological, and epigenetic changes in the brain using inducible brain-specific HIV-1 Tat transgenic mouse model (iTat) mice. iTat mice were fed with Doxcontaining diet for an extended period of 12 months and first analyzed for the behavioral changes
Summary
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. We took advantage of the doxycycline-inducible brainspecific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Using the doxycycline-inducible brainspecific HIV-1 Tat transgenic mouse model, we and others have shown that Tat alters autophagy, ER stress, lysosomal exocytosis, neurite growth, and neurogenesis [55,56,57,58,59] Besides these changes, Tat has been shown to induce abnormal behaviors in mice and rats, such as learning and memory deficits, sensorimotor impairment, anxiety, and depressive-like behavior [6069], which are accompanied by neuropathological changes such as astrocytosis and compromised neuronal integrity [32, 52, 62, 67]. We performed a series of behavioral tests, analyzed astrocyte activation and neuronal integrity by assessing GFAP, synaptophysin (SYP), and post-synaptic density protein 95 (PSD 95) expression in the brain, and performed genomic DNA methylation analysis
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