Viruses usurp the host transcriptional machinery to ensure their survival and the majority of viral mRNAs is synthetized by host RNAPII ^[1][2][4,60]. Moreover, it has been demonstrated that some v-ncRNAs, synthetized by DNAviruses, such as adenovirus-derived virus-associated RNAs (VA RNAs) and Epstein-Barr early RNAs (EBERs), are transcribed by host RNAPIII, with the characteristic of being not widespread rather expressed at high copy numbers in infected cells ^[3][8]. A different scenario involves the RNAviruses, double stranded (ds) and single positive/negative stranded (+ss or -ss, respectively), which encode for a RNA-dependent RNA polymerase (RdRp) ^[4][61]. Furthermore, some v-ncRNAs are not generated from canonical pathways; they instead derive from degradation of a unique viral mature sequence processed by host cellular machineries. For example, flavivirus RNA is degraded by RNases exoribonuclease 1 (XRN1) in host cells and this process represents a defense mechanism. In this regard, flavivirus has developed a particular RNA structure to alter XRN1 activity and to produce a large amount of degraded intermediates termed sfRNAs. These molecules are considered v-ncRNAs operating in the virus infection ^[5][13]. In the last decade, it has emerged the concept that the sequences discarded during splicing (stable intronic sequence RNAs, sisRNAs) may play physiologic roles, and this phenomenon appears to be very suitable for viruses that naturally have genomes with limited dimensions. Indeed, v-ncRNAs comprise of sisRNAs, were first discovered in the herpes simplex virus 1 (HSV-1) ^[6][62]. During latency phase, HSV-1 produces high quantities of LAT ncRNA and its respective excised introns persist and accumulate to high levels in infected cells acting as sisRNAs ^[6][7][62,63]. Although negative-sense RNA viruses do not replicates in the nuclear compartment, it has been shown that also human metapneumovirus (hMPV) produce several v-ncRNAs and, due to the fact that the transcription and replication of hMPV occur in the cytoplasm, cytoplasmic RNase as the XRN1 may be involved in the biogenesis of hMPV-derived ncRNAs ^[8][9][58,59]. In addition, different negative-strand RNA viruses including vesicular stomatitis virus (VSV), rabies virus (RABV) and influenza A virus (IAV), produce subgenomic v-ncRNAs. They were shown to interact with the viral RNA polymerase to regulate the switch from mRNA synthesis to viral genome replication influencing viral life cycle ^[10][11][64,65].

V-ncRNAs act as substrates for RNase Dicer, with the products being incorporated into argonaute-containing RNA-induced silencing complexes (RISCs) ^[12][66]. As a consequence of this process, and due to the high copy number of v-ncRNAs in infected cells, cellular miRNA biogenesis may be significantly altered ^[13][67]. Another herpesvirus that produce v-ncRNAs is Herpesvirus Saimiri (HVS) ^[14][15][68,69]. Recently, different v-ncRNAs derived from HVS were discovered to interact and down-regulated host miRNAs including miR-27, miR-16, and miR-142-3p and, with an antisense RNA-based mechanism ^[16][70].

It has been also demonstrated that some viruses use v-ncRNAs as scaffold for transcriptional factors recruitment. The EBV encoded EBER2, for example, acts as a transacting guide to promote its own transcription ^[17][71]. Collectively, all the above-reported mechanisms are just some examples of how viruses have developed strategies with the final scope of taking over the transcriptional machinery and promote viral replication.

As viruses are perfect parasites, it seems obvious that killing the host is not the best strategy for self-propagation. For this reason, viruses have developed different ways in order to influence host cell survival and block apoptosis as essential components of the cell response to injury ^[18][72]. Among Adenovirus Virus-Associated (VA) RNAs, mivaRNAI-138 can inhibit TIA-1 mRNA, a well known factor that activates apoptosis ^[19][73]. Moreover, VA RNA I is involved in the selective translation of viral mRNAs and suppression of host cell protein translation. Indeed, this ncRNA inhibits both the cleavage of double-stranded RNA and the protein kinase R (PKR), which when activated, is responsible for the phosphorylation and activation of eIF-2 (a factor capable of inhibiting protein synthesis in cells infected by virus) ^[20][74]. The latency associated non coding transcript (LAT) coded by herpes simplex virus 1 (HSV-1), exerts anti-apoptotic effect ^[21][75] and inhibits the expression of viral early genes to maintain latency by down regulating both TGF-β1 and SMAD3 expression ^[22][76]. LAT seems to play a crucial role also for Herpes simplex virus 2 (HSV-2). Indeed, it has been demonstrated as HSV-2-produced LAT inhibits apoptosis and maintains latency via LAT-encoded microRNAs (miR-H3, miR-H4-3p, miR-H4-5p, miR-H24 and miR-H19) providing protection against apoptosis induced by ActD ^[23][77]. EBV miRNAs can give a growth advantage in infected cells and therefore contribute to cell transformation both in vitro and in vivo ^[24][25][26][78,79,80]. In particular, pro-apoptotic genes like CASP3, PUMA and P53 are EBV’s miRNA targets ^[27][28][29][81,82,83]. CASP3 is also a reported target of KSHV miRNAs, miR-K12-1, K12-3 and K12-4-3p, thus reducing apoptosis ^[30][84]. Kshv-miR-K12-1 targets p21, a key tumor suppressor and inducer of cell cycle arrest, controlling cell survival and proliferation ^[31][85]. Another DNA virus, MCPyV produces a 2.7-kb RNA (β2.7) capable of preventing mitochondria-induced apoptosis ^[32][86]. Besides, it has been demonstrated that in infected mosquitoes by ZIKV, member of Flaviviridae family, the presence of sfRNA facilitates ZIKV infection and transmission by inhibiting apoptosis through the regulation of CASP7 ^[33][87]. It is also remarkable that human CMV, EBV, and KSHV have been shown to encode miRNAs, hcmv-miR-UL112-1, ebv-miR-BART-17-5p and kshv-miR-K5 respectively, which target the same pro-apoptotic gene: BclAF1 ^[34][35][36][88,89,90]. The miRNAs target sites are different for each v-miRNAs underlying the crucial role that BclAF1 plays in the life cycle of diverse herpesviruses and how different viral miRNAs may converge on similar targets without depending on the same conserved target sites ^[37][91].

Once the virus has took over the translational machinery and has assured the life host mainteinance, the following step is to maintain itself in a replicating yet not distruptive infectious status. HIV-1 v-ncRNAs, by repressing the polycomb gene EZH2, the DNA methyltransferase DNMT3a and the histone deacetylase HDAC1, modulate HIV-1 latency through epigenetic modulation ^[38][39][45,92]. The expression of HSV-1 sisRNAs, maintains viral infection by inhibiting apoptosis and silencing viral lytic gene expression through modification of the viral promoters ^[40][41][93,94]. In human and murine citomegalovirus (CMV) other sisRNAs have been identified, and these molecules seem to be involved in the progression from acute to persistent infection ^[42][95]. Recently, sisRNAs were identified also in Epstein–Barr virus (EBV) ^[43][96] and these molecules, including EBV sisRNA-1, were related with oncogenic latency processes ^[44][97]. In human B cells infected with KSHV, v-ncRNAs are mainly represented by nuclear polyadenylated (PAN) RNAs ^[45][46][98,99] that interact with demethylases JMJD3 and UTX ^[47][100]. Furthermore, it has been shown that PAN RNA also binds to the KSHV latency-associated nuclear antigen (LANA), and this interaction could be involved in the virus reactivation from latency phase ^[48][101]. Besides, hcmv-miR-UL70 may regulate MAPK signaling, focal adhesions and gap junctions’ pathways affecting epithelial cell migration and adhesion ^[49][102]. Hcmv-miR-UL112 downregulate the major immediate–early gene IE72 leading to latency through a decreased expression of viral genes involved in replication ^[50][103]. Moreover, hcmv-miR-UL112 induces proliferation of endothelial cells by up-regulating MAPK pathways or genes involved in cell growth including TSPYL2, FXYD2, TAOK2, ST7L, and TP73 ^[51][52][104,105]. The latter mechanism could represent the way by which human CMV induces endothelial dysfunction in CMV-mediated vascular diseases. Furthermore, ebv-miR-BART8-3p and ebv-miR-BART13 targets RNF38 (an E3 ubiquitin-protein ligase able to ubiquitinate p53) and NKIRAS2 (NF-kB Inhibitor) respectively ^[53][54][55][106,107,108], whereas ebv-miR-18-5p suppresses MAPK signaling by targeting MAP3K2, with consequent regulation of lytic viral replication ^[56][109]. Also, the NF-κB pathway is regulated by KSHV’s miRNAs. Indeed, kshv-miR-K1 and kshv-miR-K12-1 inhibit viral lytic replication by down-regulating IκB and activating NF-κB signaling ^[57][110]. Kshv-miR-K12-4-5p instead targets retinoblastoma Rbl2 protein and regulates the epigenetic state of infected cells ^[58][111].

One of the main processes that viral infection can, either directly or indirectly, cause in host cells, is cell transformation. This process is referred to malignant transformation with typical phenotypic changes including loss of contact inhibition, acquisition of anchorage-independent cell growth, and cell immortalization. All together, these processes are favorable for the viral propagation. Therefore, viruses lead to cellular transformation by their ability to deregulate gene/protein expression with consequent alteration of cell cycle ^[59][53]. Interestingly, it has been shown that KSHV PAN RNA could maintain cellular transformation by affecting cellular gene expression that results in an enhanced growth phenotype with an increased survival ^[60][54]. In EBV, EBERs 1 and 2 regulate a variety of host cell genes including protein kinase, cell adhesion, regulation of apoptosis, and receptor signaling ^[61][112] and, in particular EBER-1 enhance host cell protein synthesis by blocking the activation of PKR ^[62][113]. Furthermore, EBER-2 but not EBER-1 plays a critical role in viral-induced growth transformation in EBV-infected B cells ^[63][57]. These findings bring to light that EBERs are potentially involved in the cell transformation in EBV-associated malignancies. Recently it has been shown that the overexpression of an EBV miRNA, ebv-miR-BART11, is involved in epithelial-mesenchymal transition (EMT) through the downregulation of FOXP1 ^[64][114], while ebv-miR-BART7-3p enhanced loss of epithelial markers and gain of mesenchymal features in neural progenitor cells (NPC) by targeting PTEN and thus affecting PI3K/Akt/GSK-3β signaling pathway ^[65][115]. Another study on NPC cells showed ebv-miR-BART8-3p plays a key role in EMT through the targeting RNF38 via the activation of NF-κB and Erk1/2 signaling pathways ^[54][107]. Furthermore, mTOR signaling, a key pathway for KSHV to induce transformation ^[66][116], is activated when KSHV miRNAs target mTOR inhibitory factor CASTOR1 ^[67][117]. Even if extremely appealing, the v-ncRNAs roles played in these processes have not being fully cleared. Much is known about viral proteins and their functions, while for v-ncRNAs, there are many descriptive yet not functional studies. So there is a plethora of studies that correlate with different viral infection the change of host ncRNAs expression rather than the v-ncRNAs. This happens mostly when the attention is focused on the EMT of the host cell, in order to identify perhaps the key passage involved in the cell transformation. For example, hsa-miR-20b, -miR-34a, -miR-218, -miR-29a and -miR-146a have been described as regulated by HPV18 E6/E7 and have been involved in initiation and progression in HPV related cervical cancer ^[68][69][118,119].