**3. Role of miRNAs in HSV replication**

miRNAs play a huge role in the crosstalk between the virus and the host. There are certain viral and cellular miRNAs that regulate the host responses to a viral infection as well as the progression of infection. Both the viral and the cellular miR-NAs are capable of regulating the host and the viral mRNAs. Some of the miRNAs that have been identified to be involved during the HSV-1 infection have a direct or indirect impact on the viral replication. These cellular miRNAs may directly target the HSV genome or are manipulated by the HSV through the viral proteome/ transcriptome [23]. HSV-1 infected HeLa cells have shown a downregulation of the miR-649 cellular miRNA that targets a ubiquitously expressed cytoplasmic protease, MALT-1, which activates the NF-κB signaling (**Figure 2**). Since NF-κB signaling inhibits HSV-1 replication, the downregulation of miR-649 elevates the expression of MALT-1, increasing the restriction on HSV-1 replication [24]. Similarly, another cellular miRNA which is involved in the suppression of HSV-1 replication is miR-101 (**Figure 2**). The HSV- viral immediate early protein ICP4 directly binds to the promoter of miR-101 to increase the expression of miR-101 in the infected cells thereby decreasing the expression levels of its target GRSP1, which is a scaffolding

#### **Figure 2.**

*miRNAs in HSV replication: The figure describes the mode of action of the various cellular miRNAs (green) and the viral miRNAs (blue) that regulate the HSV replication. While the cellular miRNAs, miR-649,* −*101,* −*23a,* −*373 and the viral miRNA, miR-H6 block the HSV replication, the cellular miRNA, miR-155 and the viral miRNA, H-27 promote the HSV viral replication. Both the viral and the cellular miRNAs regulate the host as well as the viral gene expression to modify the replication process either as a host response tying to fight the infection or to establish the infection within the host. Pointed arrowheads indicate progression of an event while blunt arrowheads indicate blockade of an event.*

#### *Herpesviridae and microRNAs DOI: http://dx.doi.org/10.5772/intechopen.100370*

protein that may be involved in the polarization of epithelial cells. GRSP1 directly bind to the HSV-1 p40 and increases the replication of HSV-1. With enhanced suppression of GRSP1, the replication of HSV-1 is hindered. Although it seems surprising that HSV auto-downregulates its replication, it may be a necessary step for the virus to prevent host cell death due to lysis, therefore, maintaining a permissive milieu for virus harboring and replication within the cells [25]. Also, miR-101 can target ATP5B, a subunit of the ATP synthase, to restrict the HSV-1 replication [26]. These studies depict that a single miRNA such as miR-101 could regulate multiple targets to restrict the viral replication. In a study conducted by Shabani et al., a macrophage miR-7704, was capable of reducing the HSV-1 replication in HeLa cells [27]. Another cellular miRNA, miR-23a which targets the Interferon regulatory factor-1 (IRF-1), involved in innate antiviral immunity, is upregulated, so as to escape the host immune responses [28]. Also, a direct suppressor of IRF-1, miR-373, enhances HSV-1 replication by supressing the interferon stimulatory gene responses (**Figure 2**) [29]. Increased expressions of miR-155, a miRNA which could epigenetically increase the transcription of the serine/arginine-rich splicing factor 2 (SRSF2), enhances the HSV-1 replication, due to SRSF2- mediated transcriptional activation of the HSV-1 genes (**Figure 2**) [30]. Some HSV-1 viral miRNAs have also been studied that regulate the virus's replication. HSV-miR-H6, a viral miRNA which is generated profusely during HSV-1 infections, reduces HSV-1 replication by downregulating the viral protein ICP4 (**Figure 2**) [31]. Also, H-27 targets KLHL24 which is a transcriptional repressor (**Figure 2**). Therefore, increase in H-27 expression does not allow KLHL24 to suppress the HSV-1 immediate early and early gene expression, thus, promoting HSV-1 replication [23, 32].
