The inhibition of microRNAs by HIV-1 Tat suppresses beta catenin activity in astrocytes

Luca Sardo, Priyal R. Vakil, Weam Elbezanti, Anas El-Sayed, Zachary Klase

Long term infection with HIV-1, even in the context of therapy, leads to chronic health problems including an array of neurocognitive dysfunctions. The viral Tat protein has previously been implicated in neuropathogenesis through its effect on astrocytes. Tat has also been shown to inhibit the biogenesis of miRNAs by inhibiting the activity of the cellular Dicer protein in an RNA dependent fashion. Whether there is a mechanistic connection between the ability of HIV-1 Tat to alter miRNAs and its observed effects on cells of the central nervous system has not been well examined. Here, we examined the ability of HIV-1 Tat to bind to and inhibit the production of over 300 cellular miRNAs. We found that the Tat protein only binds to and inhibits a fraction of the total cellular miRNAs. By mapping the downstream targets of these miRNAs we have determined a possible role for Tat alterations of miRNAs in the development of neuropathogenesis. Specifically, this work points to suppression of miRNAs function as the mechanism for Tat suppression of β-catenin activity. The discovery that HIV-1 Tat inhibits only a fraction of miRNAs opens new areas of research regarding changes in cellular pathways through suppression of RNA interference. Our initial analysis strongly suggests that these pathways may contribute to HIV-1 disruption of the central nervous system.