**6.2 Kaposi's sarcoma (KS)- associated herpesvirus (KSHV) miRNAs**

KSHV miRNAs regulate the viral mRNAs directly as well as indirectly via the regulation of the cellular mRNAs (**Figure 4**). Certain viral miRNAs participate to establish latency in the KSHV-infected cells. miR-K7 and miR-K9–5p target the KSHV RTA protein, which acts as a switch between the lytic and latency cycles [77, 78]. Also, miR-K11 and miR-K3 function to maintain latency by indirectly suppressing the RTA transcript [79–81]. Another latency-inducing miRNA is the miR-K4-5p which inhibits the retinoblastoma-like protein-2 (RBl2) expression due to which the DNMT1 (methylation enzyme) expression increases. Methylation of the RTA promoter by DNMT1 suppresses RTA expression, inducing latency in the cells [79, 81]. Angiogenesis is an important event in the KSHV infection as it allows the spread of the latency-induced malignancies. GRK2 which regulates the AKT/CXCR2 pathway to establish a reciprocity between viral replication and induction of angiogenesis, is targeted by miR-K3 to decrease viral replication and induce angiogenesis, thus establishing latency [82]. Contradictorily, BCLAF1, Bcl 2-associated factor-1, is the common target for miR-K5, miR-K9 and miR-K10a/b and has been known to

trigger the lytic infection cycle [83] miR-K5 and K9 also suppress the TLR-mediated production of the inflammatory cytokines IL-6, IL-8 and IL-1α by directing interfering with the intermediates, MyD88 and IRAK-1, respectively [84, 85]. The KSHV miRNAs also attempt to inhibit apoptosis and promote cell survival, which is crucial for both malignancy and latency. Therefore, miR-K1, -K3 and -K4 inhibit apoptosis by directly targeting the Caspase-3 protease [86] miR-K10, the viral orthologue of hsa-miR-142-3p, targets TGF-β to promote cell survival and cellular transformation [87, 88] miR-K10a is also the negative regulator of the TWEAK receptor, which is the receptor for the TNF-like weak inducer of apoptosis, thereby, inhibiting apoptosis as well as downregulating the production of IL-8 and MCP-1 to contribute to the KS progression [89] miR-K1 also promotes cell cycle progression by inhibiting p21 [90]. Another target for miR-K1, IκBα, which usually retains NF-κB in the cytoplasm by blocking the nuclear localization signals, is constrained to promote latency and survival of the transformed cells [91]. Activation of NF-κB also inhibits the Warburg effect leading to the declined expressions of GLUT-1 and GLUT-3, suggesting the significance of the metabolic regulation for the proliferation of the KS cells [92]. Just as miR-155 have been considered as the regulatory epicenter of various cancers and viral infections, the KSHV miRNA, miR-K11 mimics some of the functions of this cellular miRNA. miR-K11 blocks the C/EBPβ resulting in the enhanced, IL-6 mediated proliferation of the B cells [93]. It also targets JARID2 leading to increased B cell transformation [94]. Moreover, miR-K11 also inhibits the IFN type I signaling by directly targeting IKKε mRNA [95, 96]. Thus, the generation of cellular miRNA orthologues by the herpesviruses is clearly evident of its co-evolution with its host, such that it diverts the cellular machinery towards its own viral processes while hiding itself efficiently from the host responses.
