Abstract: Reversible synaptodendritic injury and glial activation have emerged as important phenotypes and correlates of HAND. Furthermore, persistent inflammation that has been implicated as a major underlying factor in the progression and pathology of HAND, is likely attributable to the fact that following virus infection and formation of the proviral DNA, antiretroviral therapy (ART) has no effect on the expression of viral gene products such as Tat or gp120 that are lurking in tissues such as the CNS. Intriguingly, similar to HIV+ subjects on ART, SIV- infected rhesus macaques on ART also demonstrate loss of synaptophysin, increased glial activation and dysregulation of various signature microRNAs (miRs). MiR-mediated regulation of disease pathogenesis represents an evolving area of research that has ramifications for the identification of potential therapeutic targets for various neurodegenerative disorders, for which, currently there exists no cure. Parallel to the advances made in miRNA research, there has also been the advent of the field of extracellular vesicles (EVs). EVs represent an important mode of intercellular communication, by serving as conduits for the transfer of membrane and cytosolic proteins, lipids and RNA (including miRs), between cells. Based on miRNA array data obtained from the brains (basal ganglia) of SIV+ macaques, we hypothesize that HIV proteins modulate HAND neuropathology via two complementary miR-associated mechanisms: a) HIV Tat-exposed astrocytes upregulate the expression and release of miRs regulating synaptic plasticity in the EVs, which, following uptake by the neurons, cause synaptodendritic injury and, b) HIV Tat-exposed astrocytes also upregulate the expression and release of inflammation related miRs in the EVs, which, following uptake by the microglia (Mg), leads to their activation via the TLR7-dependent pathway. The innovative aspect of this proposal is based on our unique observation that HIV-protein exposed astrocytes release EVs containing a signature cargo of miRs, which are taken up by neighboring neurons and Mg to induce synaptodendritic injury and activation, respectively. These experiments will be brought full circle with an examination of functional studies aimed at uncovering the underlying mechanisms of EV/miR-mediated synaptodendritic injury and glial activation in a Tat inducible transgenic model.