Dengue is a mosquito-borne viral disease (arboviral) caused by the Dengue virus. It is one of the prominent public health problems in tropical and subtropical regions with no effective vaccines. Every year around 400 million people get infected by the Dengue virus, with a mortality rate of about 20% among the patients with severe dengue. The Dengue virus belongs to the Flaviviridae family, and it is an enveloped virus with positive-sense single-stranded RNA as the genetic material. Studies of the infection cycle of this virus revealed potential host targets important for the virus replication cycle. Here in this review article, we will be discussing different stages of the Dengue virus infection cycle inside mammalian host cells and how host proteins are exploited by the virus in the course of infection as well as how the host counteracts the virus by eliciting different antiviral responses.

Hepatitis C virus (HCV)-mediated chronic liver disease is a global health problem, and inflammation is believed to be an important player in disease pathogenesis. HCV infection often leads to severe fibrosis/cirrhosis and hepatocellular carcinoma, although the mechanisms for advancement of disease are not fully understood. The proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 have critical roles in establishment of inflammation. In this study, we examined induction of IL-1β/IL-18 secretion following HCV infection. Our results demonstrated that monocyte-derived human macrophages (THP-1) incubated with cell culture-grown HCV enhance the secretion of IL-1β/IL-18 into culture supernatants. A similar cytokine release was also observed for peripheral blood mononuclear cell (PBMC)-derived primary human macrophages and Kupffer cells (liver-resident macrophages) upon incubation with HCV. THP-1 cells incubated with HCV led to caspase-1 activation and release of proinflammatory cytokines. Subsequent studies demonstrated that HCV induces pro-IL-1β and pro-IL-18 synthesis via the NF-κB signaling pathway in macrophages. Furthermore, introduction of HCV viroporin p7 RNA into THP-1 cells was sufficient to cause IL-1β secretion. Together, our results suggested that human macrophages exposed to HCV induce IL-1β and IL-18 secretion, which may play a role in hepatic inflammation.

Hepatitis C virus (HCV) is a serious global health problem and establishes chronic infection in a significant number of infected humans worldwide. Interferon (IFN) and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients, and the mechanism is not fully understood. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, including IFN signaling. To gain more insights into the role of cellular miRNAs in possible countermeasures of HCV for suppression of the host antiviral response, a miRNA array was performed by using primary human hepatocytes infected with in vitro cell culture-grown HCV. A group of miRNAs were modulated in HCV-infected primary human hepatocytes. We focused on miR-373, as this miRNA was significantly upregulated in HCV-infected primary human hepatocytes. Here, we analyzed the function of miR-373 in the context of HCV infection. HCV infection upregulates miR-373 expression in hepatocytes and HCV-infected liver biopsy specimens. Furthermore, we discovered that miR-373 directly targets Janus kinase 1 (JAK1) and IFN-regulating factor 9 (IRF9), important factors in the IFN signaling pathway. The upregulation of miR-373 by HCV also inhibited STAT1 phosphorylation, which is involved in ISG factor 3 (ISGF3) complex formation and ISG expression. The knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression and reduced HCV RNA replication. Taken together, our results demonstrated that miR-373 is upregulated during HCV infection and negatively regulated the type I IFN signaling pathway by suppressing JAK1 and IRF9. Our results offer a potential therapeutic approach for antiviral intervention. IMPORTANCE Chronic HCV infection is one of the major causes of end-stage liver disease worldwide. Although the recent introduction of direct-acting antiviral (DAA) therapy is extremely encouraging, some infected individuals do not respond to this therapy. Furthermore, these drugs target HCV nonstructural proteins, and with selective pressure, the virus may develop a resistant strain. Therefore, understanding the impairment of IFN signals will help in designing additional therapeutic modalities. In this study, we provide evidence of HCV-mediated upregulation of miR-373 and show that miR-373 impairs IFN signaling by targeting JAK1/IRF9 molecules. The knockdown of miR-373 inhibited HCV replication by upregulating interferon-stimulating gene expression. Together, these results provided new mechanistic insights into the role of miR-373 in HCV infection and suggest a new potential target against HCV infection.

Following virus infection, one of the cellular responses to limit the virus spread is induction of apoptosis. In the present study, we report role of rotavirus nonstructural protein 1 (NSP1) in regulating apoptosis by activating prosurvival pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt and NF-κB (nuclear factor κB) during early hours of infections (2 to 8 hpi). The NSP1 mutant strain A5-16 induces weak and transient activation of Akt (protein kinase B) and p65 NF-κB compared to the isogenic wild-type strain A5-13 in MA104 or HT29 cells. The weak NF-κB promoter activity or Akt phosphorylation after A5-16 infection could be complemented in cells transfected with plasmid expressing NSP1 after infection with the rotavirus A5-16 strain. In cells either infected with A5-13 or transfected with pcD-NSP1, coimmunoprecipitation of NSP1 with phosphoinositide 3-kinase (PI3K) was observed, indicating that strong activation of PI3K/Akt could be due to its interaction with NSP1. In addition, after infection with same multiplicity of infection, A5-16 showed reduced number of viral particles compared to the A5-13 strain at the end of the replication cycle. A lower growth rate could be due to weak induction of PI3K/Akt and NF-κB, since the A5-13 strain also showed reduced growth in the presence of PI3K or NF-κB inhibitors. This effect was interferon independent; however, it was partly due to significantly higher caspase-3 activity, poly-ADP ribose polymerase (PARP) cleavage, and apoptosis during earlier stages of infection with the NSP1 mutant. Thus, our data suggest that NSP1 positively supports rotavirus growth by suppression of premature apoptosis for improved virus growth after infection.

Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). The molecular events leading to HCC following chronic HCV infection remain poorly defined. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, and their deregulation is associated with different viral infections. In this study, we observed that HCV infection of hepatocytes transcriptionally downregulates miR-181c expression by modulating CCAAT/enhancer binding protein β (C/EBP-β). Reduced expression of the pri-miR-181c transcript was noted following HCV infection. In silico prediction suggests that homeobox A1 (HOXA1) is a direct target of miR-181c. HOXA1 is a member of the homeodomain-containing transcription factor family and possesses pivotal roles in normal growth, development, and differentiation of mammalian tissues. Our results demonstrated that HOXA1 expression is enhanced in HCV-infected hepatocytes. Exogenous expression of the miR-181c mimic inhibits HOXA1 and its downstream molecules STAT3 and STAT5, which are involved in cell growth regulation. Interestingly, overexpression of miR-181c inhibited HCV replication by direct binding with E1 and NS5A sequences. Furthermore, accumulation of HCV genotype 2a RNA with miR-181c was observed in an RNA-induced silencing complex in Huh7.5 cells. Our results provide new mechanistic insights into the role of miR-181c in HCV-hepatocyte interactions, and miR-181c may act as a target for therapeutic intervention. IMPORTANCE Chronic HCV infection is one of the major causes of end-stage liver disease, including hepatocellular carcinoma. An understanding of the molecular mechanisms of HCV-mediated hepatocyte growth promotion is necessary for therapeutic intervention against HCC. In this study, we have provided evidence of HCV-mediated transcriptional downregulation of miR-181c. HCV-infected liver biopsy specimens also displayed lower expression levels of miR-181c. We have further demonstrated that inhibition of miR-181c upregulates homeobox A1 (HOXA1), which is important for hepatocyte growth promotion. Exogenous expression of miR-181c inhibited HCV replication by directly binding with HCV E1 and NS5A sequences. Taken together, our results provided new mechanistic insights for an understanding of the role of miR-181c in HCV-hepatocyte interactions and revealed miR-181c as a potential target for therapeutic intervention.