MicroRNA regulation of p21 and TASK1 cellular restriction-factors enhances HIV-1 infection

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that play a central role in the regulation of gene expression by binding to target mRNAs. Several studies have revealed alterations in cellular miRNA profiles following HIV-1 infection, mostly for miRNAs involved in inhibiting viral infection. These miRNA expression modifications might also serve to block the innate HIV-1 inhibition mechanism. As a result, it is expected that during HIV-1 infection miRNAs target genes that hinder or prevent the progression of the HIV-1 replication cycle. One of the major sets of genes known to inhibit the progression of HIV-1 infection are cellular restriction factors. In this study, we identified a direct miRNA target gene that modulates viral spread in T-lymphocytes and HeLa-CCR5 cell lines. Following infection, let-7c, miR-34a or miR-124a were upregulated, and they targeted and downregulated p21 and TASK1 (also known as CDKN1A and KCNK3, respectively) cellular proteins. This eventually led to increased virion release and higher copy number of viral genome transcripts in infected cells. Conversely, by downregulating these miRNAs, we could suppress viral replication and spread. Our data suggest that HIV-1 exploits the host miRNA cellular systems in order to block the innate inhibition mechanism, allowing a more efficient infection process.

The emerging role of long non-coding RNAs in HIV infection

“…Since multiple viral genes are differentially expressed from a single promoter throughout the various stages of the HIV infection cycle, alternative regulatory mechanisms stretching beyond cellular transcription factors must exist to ensure such transcriptional specificity. Recent research studies have pointed to ncRNAs as essential elements in the regulatory network that controls HIV expression (Chen et al, 2014; Farberov et al, 2015; Imam et al, 2015; Patel et al, 2014; Saayman et al, 2014; Schopman et al, 2012; Sung and Rice, 2009; Zhang et al, 2013; Zhang et al, 2014). These regulatory ncRNAs have been demonstrated to originate from both the virus as well as from host cells.…”

“…Working in tandem, miR-34a and miR-124a inhibit TASK1 mRNA (Farberov et al, 2015). TASK1, a mammalian potassium channel, contains high structural homology with the HIV protein Vpu.…”

Hsa-let-7c-5p augments enterovirus 71 replication through viral subversion of cell signaling in rhabdomyosarcoma cells

“…Hsa-let-7c is downregulated in most cancers and plays crucial roles in carcinogenesis and cancer metastasis [21–23]. In addition, it has been reported to be upregulated in response to RNA virus infection and to affect viral replication [24–26]. The miRNA let-7c has been shown to inhibit influenza virus replication by degrading viral gene M1 (+) cRNA in human lung epithelial cells [24].…”

“…Further, let-7c has been reported to suppress viral replication through targeting of the transcription factor BACH1 in dengue virus-infected human hepatoma Huh-7 cells [25]. Moreover, this miRNA may enhance HIV-1 infection by downregulating the cellular restriction factor p21 [26]. However, its roles in mediating virus-host interactions through the regulation of host pathways have not been previously investigated.…”

MicroRNA-555 has potent antiviral properties against poliovirus

“…Increasing evidence suggests that miRNAs have a critical role in the host-virus interaction during infection (Skalsky & Cullen, 2010;Umbach & Cullen, 2009;Wang et al, 2014). Virus infection results in expression of viral proteins known to alter cellular miRNA expression to enhance virus replication (Farberov et al, 2015;Jopling et al, 2005). However, miRNAs expressed by the infected host cell can act as a countermeasure to suppress virus replication through directly targeting viral RNA (Müller & Imler, 2007;Trobaugh2015;Hu et al, 2012;Huang et al, 2015).…”