HIV-1 infection of the central nervous system (CNS) occurs in a majority of AIDS patients and causes a variety of neurologic dysfunction and neuropathologies generally termed neuroAIDS. Microglia/macrophages and astrocytes to a less extent are the main HIV-1 target cells in the CNS, whereas neurons are rarely infected by HIV-1 but mostly affected in HIV/neuroAIDS. Therefore, several indirect mechanisms have been proposed for HIV/neuroAIDS pathogenesis. Among them is HIV-1 Tat protein. We have shown that Tat expression in the absence of HIV-1 infection is sufficient to cause neurobehavioral abnormalities and pathologies similar to most of those noted in HIV/neuroAIDS. Moreover, we have shown that Tat activates glial fibrillary acidic protein expression in astrocytes and contributes astrocyte dysfunction and subsequent neuron death. In the preliminary studies, we have found that Tat expression in astrocytes induces miR-132 expression and secretion in the form of exosomes and alters neurite growth and neuron survival. Importantly, we have also obtained preliminary evidence to link the cerebrospinal fluid (CSF) miR-132 levels to HIV/neuroAIDS pathogenesis. As a logical extension of our studies, we propose to further dissect the miR-132 function in astrocyte-mediated Tat neurotoxicity and HIV/neuroAIDS pathogenesis. Besides, we will determine the feasibility of using the CSF miR-132 level as a novel HIV/neuroAIDS biomarker. Thus, the underlying hypothesis for the current proposal is that Tat adversely affects astrocyte and neuron function and neuronal survival through regulation of miR-132 and its target genes. In other words, miR-132 is not only a mediator but also an indicator of Tat neurotoxicity and HIV/neuroAIDS pathogenesis. To test this hypothesis, we propose to address the following interrelated specific aims: (1) To characterize the mechanisms of Tat-induced miR-132 expression in astrocytes; (2) To determine effects of Tat-induced miR-132 expression on astrocytes; (3) To elucidate the mechanisms of miR-132-mediated Tat neurotoxicity; and (4) To investigate the potential of using CSF miR-132 as an HIV/neuroAIDS biomarker. We will use a combined molecular, cellular, biochemical, and genetic approach including use of primary mouse astrocyte cultures and neuron cultures, Tat transgenic and miR-132 knockout mice, primary human fetal brain cultures, brain tissues and CSF samples of HIV-1 cohorts in our studies. The answers sought have fundamental significance for understanding of this critical and pervasive protein HIV-1 Tat, and its role in HIV/neuroAIDS pathogenesis. In addition, these answers shall also aid in identification of HIV/neuroAIDS biomarkers and development of anti-HIV/neuroAIDS therapeutic strategies. The enormous amount of information available on HIV-1 Tat, HIV infection of astrocytes, and roles of miR-132/target genes in neurodegenerative diseases, the results obtained from our preliminary studies, and the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) resources make accomplishment of these aims practical.
HIV-1 infection often causes a number of brain diseases and affects 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 the host factors that are important for the disease progression and then use the knowledge acquired to develop new markers to monitor the disease progression and treatment response and develop new therapeutics.
