Abstract
BackgroundAlthough highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality in HIV patients, virus continues to reside in the central nervous system (CNS) reservoir. Hence, a complete eradication of virus remains a challenge. HIV productively infects microglia/macrophages, but astrocytes are generally restricted to HIV infection. The relative importance of the possible replication blocks in astrocytes, however, is yet to be delineated. A recently identified restriction factor, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), restricts HIV infection in resting CD4+T cells and in monocyte-derived dendritic cells. However, SAMHD1 expression and HIV-1 restriction activity regulation in the CNS cells are unknown. Though, certain miRNAs have been implicated in HIV restriction in resting CD4+T cells, their role in the CNS HIV restriction and their mode of action are not established. We hypothesized that varying SAMHD1 expression would lead to restricted HIV infection and host miRNAs would regulate SAMHD1 expression in astrocytes.ResultsWe found increased SAMHD1 expression and decreased miRNA expression (miR-181a and miR-155) in the astrocytes compared to microglia. We report for the first time that miR-155 and miR-181a regulated the SAMHD1 expression. Overexpression of these cellular miRNAs increased viral replication in the astrocytes, through SAMHD1 modulation. Reactivation of HIV replication was accompanied by decrease in SAMHD1 expression.ConclusionsHere, we provide a proof of concept that increased SAMHD1 in human astrocytes is in part responsible for the HIV restriction, silencing of which relieves this restriction. At this time, this concept is of theoretical nature. Further experiments are needed to confirm if HIV replication can be reactivated in the CNS reservoir.
Highlights
HIV-1 infection of astrocytes results in an initial productive, non-cytopathogenic infection that diminishes to a poorly productive, persistent infection [1,2]
HIV-1 infection in astrocytes peaked at day 5 (450 pg/ml), which diminished at day 7 and remained low from day 10 onwards (Figure 1A)
Our observation is in agreement with previous reports, which showed that HIV-1 infection of astrocytes results in an initial productive, non-cytopathogenic infection that diminishes to a poorly productive, persistent infection leading to a latent state [1,2,32]
Summary
HIV-1 infection of astrocytes results in an initial productive, non-cytopathogenic infection that diminishes to a poorly productive, persistent infection [1,2]. Infected astrocytes initiate productive infection of HIV-permissive blood-derived cells in coculture experiments [7,8]. The astrocytic reservoir protected from HAART is capable of initiating new Pilakka-Kanthikeel et al Journal of Neuroinflammation (2015) 12:66 infections upon treatment discontinuation and constitutes an important hindrance to HIV clearance from the central nervous system (CNS) [7,16,17]. Highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality in HIV patients, virus continues to reside in the central nervous system (CNS) reservoir. SAMHD1 expression and HIV-1 restriction activity regulation in the CNS cells are unknown. We hypothesized that varying SAMHD1 expression would lead to restricted HIV infection and host miRNAs would regulate SAMHD1 expression in astrocytes
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