HIV-1 Tat-mediated microglial inflammation involves a novel miRNA-34a-NLRC5-NF?B signaling axis.

ABSTRACT: While the advent of combination antiretroviral therapy (cART) has dramatically increased the lifespan of people living with HIV-1 paradoxically, the prevalence of NeuroHIV in people treated with cART is on the rise. It has been well documented that despite the effectiveness of cART in suppressing viremia, CNS continues to harbor viral reservoirs with persistent low-level virus replication. This, in turn, leads to the presence and accumulation of early viral protein - HIV-1 Tat, that is a well-established cytotoxic agent. In the current study, we demonstrated that exposure of mouse microglia to HIV-1 Tat resulted both in a dose- and time-dependent upregulation of miRNA-34a, with concomitant downregulation of NLRC5 (a negative regulator of NF?B signaling) expression. Using bioinformatics analyses and Argonaute immunoprecipitation assay NLRC5 was identified as a novel target of miRNA-34a. Transfection of mouse primary microglia with miRNA-34a mimic significantly downregulated NLRC5 expression, resulting in increased expression of NF?B p65. In contrast, transfection of cells with miRNA-34a inhibitor upregulated NLRC5 levels. Using pharmacological approaches, our findings showed that HIV-1 Tat-mediated microglial activation involved miRNA-34a-mediated downregulation of NLRC5 with concomitant activation of NF?B signaling. Reciprocally, inhibition of miRNA-34a blocked HIV-1 Tat-mediated microglial activation. In summary, our findings identify yet another novel mechanism of HIV-1 Tat-mediated activation of microglia involving the miRNA-34a-NLRC5-NF?B axis. These in vitro findings were also validated in the medial prefrontal cortices of HIV-1 transgenic rats as well as in SIV-infected rhesus macaques. Overall, these findings reveal the involvement of miRNA-34a-NLRC5-NF?B signaling axis in HIV-1 Tat-mediated microglial inflammation.

SUBMITTER: Periyasamy P 

PROVIDER: S-EPMC6660398 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature