Combination antiretroviral therapy (cART) has considerably prolonged the lifespan of HIV-infected individuals and changed the landscape of the HIV/AIDS disease. However, latent HIV in the cells/tissues has prevented from achieving a functional cure or complete eradication. Limited access to cART and the ability of HIV to establish latent infection have made the central nervous system (CNS) unique HIV reservoirs. Microglia/macrophages are the main target cells for HIV infection in the CNS and all can be productively, latently or persistently infected. In contrast, astrocytes are infected but in a restricted manner; our understanding of these cells as HIV latent reservoirs and their roles of HIV latency in HIV/neuroAIDS is quite limited. We have recently found that cell-cell contact leads to successful HIV infection of astrocytes and establishment of HIV latency in these cells with an extremely low level of ongoing HIV replication. In addition, we have found that expression of HIV early gene Tat in astrocytes induces miR-132 and down-modulates methyl CpG-binding protein 2 (MeCP2), a chromatin-remodeling epigenetic factor and causes neurotoxicity through miRNA- containing exosomes. Moreover, we have shown that cocaine activates HIV replication in HIV latently infected astrocytes through miR-132 expression and that Tat expression is linked to establishment of HIV latency in astrocytes. Lastly, we have obtained the preliminary data that miR-132 expression in the cerebrospinal fluid (CSF) is elevated in HIV-infected subjects with minor cognitive and motor disorder. As a logical extension of our published and preliminary studies, we propose to characterize HIV infection and latency in astrocytes and their contribution to astrocyte function and HIV/neuroAIDS in the era of cART. The underlying hypothesis of this proposal is that HIV-infected astrocytes constitute latent HIV reservoirs in the CNS and directly contribute to HIV/neuroAIDS. To test this hypothesis, we propose to address the following four interrelated specific aims: (1) To characterize cell-cell contact-mediated HIV infection of astrocytes; (2) To elucidate molecular mechanisms of HIV latency in astrocytes; (3) To determine effects of latent HIV infection on astrocytes and neurons; and (4) To identify CSF biomarkers for HIV latency in the brain. We will use a combined molecular, cellular, biochemical, and genetic approach including use of primary mouse cortical astrocyte cultures and neuron cultures, doxycycline-inducible brain-specific HIV Tat transgenic mice (iTat), primary human fetal brain/astrocyte cultures, brain tissues and CSF samples of HIV-1 cohorts in our studies. We anticipate that this proposal will allow us to determine the regulatory mechanisms of HIV latency in astrocytes and the significance of these cells as HIV reservoirs in the ear of cART and in the context of cocaine abuse. The findings will likely inform control and eradication strategies for the HIV reservoirs in the CNS. The enormous amount of information available on HIV infection and pathogenesis in the CNS/astrocytes and HIV latency in the periphery and the results obtained from our preliminary studies make accomplishment of these aims practical.
HIV-1 infection and abuse of drugs such as cocaine often cause a number of brain diseases and affect the ability of people to care for themselves and thus the quality of their daily life. The social and economic impact cannot be overemphasized. The current study seeks to have a better understanding of how HIV and drug abuse interact in the era of combination antiviral therapy and then use the knowledge acquired to develop new markers to monitor the disease progression and treatment response and develop new therapeutics.
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