LncRNAs, like growth arrest-specific 5 ( GAS5), BST2 interferon stimulated positive regulator ( BISPR), lncRNA#32/ LUARIS, and lncITPRIP-1 can suppress HCV replication by different mechanisms. They may function in the HCV life cycle, the antiviral immune response induced by HCV, or in HCV immune escape, finally exerting a proviral or antiviral role. Increasing evidence suggests that cellular lncRNAs may be deregulated in response to viral replication or to the antiviral pathways induced by infection. LncRNAs can regulate chromatin remodeling, transcription in cis or trans, translation, or serve as enzyme cofactors. Ĭonstituting about 65% of the human transcriptome, long non-coding RNA (lncRNA) is defined as RNA with more than 200 nucleotides in length and lacking protein coding capacity or only containing small open reading frames (ORFs). Moreover, HCV related exosomes also contribute to the immune escape. Autophagy induced by HCV might also be involved in the suppression of type I IFN production. It was shown that the ineffectiveness of the innate immune response can be achieved by cleavage of MAVS by NS3/4A protease, by an ISG translation block mediated by the noncanonical cellular sensors dsRNA-activated protein kinase R ( PKR) and DEAD box RNA helicase 3 ( DDX3X), or by ISGs like ubiquitin specific peptidase 18 ( USP18) that downregulates the IFN pathway response as a negative feedback to ensure homeostasis of the cellular immune response. The co-existence of high viral loads and high ISG expression reflects the failure of the innate immune response in clearing HCV, suggesting strategies used by HCV to evade the host immune response. HCV remains a global health issue affecting approximately 2% of the global population. In spite of activated immune response, 70–80% of infected patients develop chronic infection without clearance of HCV, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Only combined ISGs can induce a strong antiviral response, while the effect of a single ISG is weak. IFN signaling and the subsequent expression of ISGs are central in this antiviral defense. Antiviral ISGs may target many steps in the HCV life cycle to limit viral replication or promote the IFN antiviral ability. After triggering the JAK-STAT signaling pathway, the final outcome of the IFN signaling is the induction of hundreds of IFN-stimulated genes (ISGs), which serve as direct effectors of the IFN antiviral defense. Upon HCV infection, specific pathogen-associated molecular patterns (PAMPs) of HCV can be sensed by different pattern recognition receptors (PRRs), like retinoic acid-inducible gene I ( RIG-I), melanoma differentiation factor 5 ( MDA5), and toll-like receptor 3 ( TLR3), leading to the production of pro-inflammatory cytokines, chemokines, and interferon (IFN), which include Type I IFN ( IFNα, IFNβ, and others), Type II IFN ( IFNγ), and Type III IFN ( IFNλ). The tightly coordinated innate immune signaling pathways in the liver provide the first and significant line of host defense against HCV, while the adaptive immune response emerges over several weeks. These events may contribute to the failure to eliminate ongoing HCV infection.ĭuring its life cycle, the cell develops several mechanisms to recognize the virus and fight against it. The latter fact is also consistent with an anti-inflammatory role of GPR55. We conclude that HCV induces lncR 8 expression, while lncR 8 indirectly favors HCV replication by stimulating expression of its neighboring gene GPR55, which in turn downregulates expression of ISGs. Furthermore, knockdown of GPR55 mRNA induces ISG expression, providing a possible link between lncR 8 and ISGs. Importantly, the effect of lncR 8 on ISGs and GPR55 precedes its effect on HCV replication. lncR 8 knockdown in Huh-7.5 cells reduced expression of the neighboring gene G protein-coupled receptor 55 ( GPR55) mRNA level at early times, and leads to increased levels of several Interferon stimulated genes (ISGs) including ISG15, Mx1 and IFITM1. After suppressing the expression of lncR 8, HCV RNA and protein were downregulated, confirming a positive correlation between lncR 8 expression and HCV replication. Of these, lncR 8( Lnc-ITM2C-1/ LOC151484) was confirmed by quantitative real-time PCR (qRT-PCR) to be upregulated early after HCV infection. Using microarrays, we identified lncRNAs with altered expression levels in HCV replicating Huh-7.5 hepatoma cells. Multiple host factors are known to play important roles in hepatitis C virus (HCV) replication, in immune responses induced by HCV infection, or in processes that facilitate virus escape from immune clearance, while yet only few studies examined the contribution of long non-coding RNAs (lncRNAs/lncRs).
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