Human immunodeficiency virus 1 (HIV-1) remains one of the most leading causes of death worldwide. HIV penetrates central nervous system (CNS) during early infection, establishing a viral reservoir. Even though astrocytes are infected by HIV, unlike microglia and brain macrophages, they are not productively infected. Non-productive infection could be significant to neuropathogenesis. Although the potent antiretroviral therapies have significantly improved the morbidity rate in HIV patients, the biggest challenge is the inability of HAART to eradicate the virus from the reservoirs. The mechanisms governing the establishment of HIV reservoir in vivo are still not fully understood. Recently identified restricton factor, SAMHD1, which hydrolyses and depletes dNTPs, has been shown to restrict HIV infection in resting CD4+ T cells and monocyte derived dendritic cells. But its role in CNS cells has not been reported yet. Inosine monophosphate dehydrogenase (IMPDH) is involved in the synthesis of dGTP, an allosteric activator of SAMHD1. In the presence of dGTP, SAMHD1 is in its active tetramer form. Our preliminary data showed higher expression level of SAMHD1 in astrocytes compared to microglia. We also found that cocaine increased IMPDH, which in turn increased viral replication in astrocytes. Based on the previous reports from literature and our preliminary data, we hypothesized that increased SAMHD1 expression and lower IMPDH in astrocytes hampers retrovirus reverse transcription, which in turn leads to non-productive infection. In this proposal, we will examine the expression and activity of SAMHD1 and IMPDH in astrocytes and microglia, its role in HIV replication and its modulation by cocaine.
Mechanisms of restrictive viral infectivity in astrocytes are yet to be elucidated. This is the first study examining (1) the role of SAMHD1 and IMPDH protein on differential HIV replication in astrocytes and microglia, and (2) the effect of cocaine on these molecules; and is of highly therapeutic significance to control HIV infection and neuroAIDS.
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