HIV-1 TAT Induces MIR-132 Expression Leading to Neurotoxicity and Aberrant Dendritic Morphology




He, Johnny
Rahimian, Pejman


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TITLE: HIV-1 Tat induces mir-132 expression leading to neurotoxicity and aberrant dendritic morphology Authors: Pejman Rahimian, Johnny He Presenter name: Pejman Rahimian Purpose: HIV-1 Tat is involved in the pruning of neurites and loss of synapses which are the most prominent pathological hallmarks of HIV-associated neurocognitive disorders (HAND). However the underlying molecular mechanisms of this synaptodendritic loss have not been elucidated. We report for the first time the induction of a brain-enriched microRNA by HIV-1 Tat protein leading to repression of significant regulating factors in dendritic arborization and synapse formation. Methods: Levels of miR-132 were quantitated in astrocyte cell lines (U373.MG), primary human and primary mouse astrocytes, and also in neurons (SH-SY5Y) following transfection with Tat plasmid and also in primary human astrocytes following infection with the VSVG-pseudotyped HIV-1 virus. Repression of miR-132 targets and involvement of CREB in miRNA induction were evaluated via Western blotting. Results: We observed significant miR-132 upregulation as the result of Tat expression in both neurons and astrocytes followed by the repression of miR-132 targets in both cell types. Activation of CREB as indicated by elevated p-CREB was observed along with Tat expression while using a Tat construct defective in CREB activation abrogated miR-132 induction by Tat. We also observed significant reduction in neuronal viability along with loss of dendritic arbor following Tat expression which correlate with the repression of miR-132 targets MecP2 and p250GAP and consequently BDNF loss. Conclusion: Our results indicate that HIV-1 Tat induces miR-132 in the brain through activation of CREB and stabilization of interaction between p-CREB and CREB-binding protein (CBP). Dysregulated miR-132 expression contributes to neurotoxicity and aberrant dendritic morphology witnessed in neurocognitive disorders associated with HIV-1 invasion of the central nervous system. Acknowledgments (ex. funding support, etc.) Neurobiology of Aging Training Grant-T32 AG020494 IACUC#: 2014/15-01-A04


Research Appreciation Day Award Winner - 2016 Department of Cell Biology and Immunology - 2nd Place Poster Award
Research Appreciation Day Award Winner - 2016 Department of Cell Biology and Immunology - Robert J. Wordinger Excellence in Virology Research Poster Presentation 2nd Place Award