Hepatitis C virus alternative reading frame protein (ARFP): Production, features, and pathogenesis

Abstract

Earlier observation suggests that hepatitis C virus (HCV) is a single‐stranded RNA virus which encodes at least 10 viral proteins. F protein is a novel protein which has been discovered recently. These studies suggest three mechanisms for the production of this protein concerning ribosomal frameshift at codon 10, initial translation at codons 26 and 85 or 87. In this study, the association between protein F and chronicity of hepatocellular carcinoma (HCC) has been reviewed. Evidence suggests that humoral immune system can recognize this protein and produce antibodies against it. By detecting antibodies in infected people, investigators found that F protein might have a role in HCV infection causing chronic cirrhosis and HCC as higher prevalence was found in patients with mentioned complications. The increment of CD4+, CD25+, and FoxP3+ T cells, along with CD8+ T cells with low expression of granzyme B, also leads to weaker responses of the immune system which helps the infection to become chronic. Moreover, it contributes to the survival of the virus in the body through affecting the production of interferon. F protein also might play roles in the disease development, resulting in HCC. The existence of F protein affects cellular pathways through upregulating p53, c‐myc, cyclin D1, and phosphorylating Rb. This review will summarize these effects on immune system and related mechanisms in cellular pathways.

Alterations in Hepatocellular Carcinoma-Specific Immune Responses Following Hepatitis C Virus Elimination by Direct-Acting Antivirals

“…An RNAseq analysis revealed that the mRNA expression level of the TbX21 gene increased after the treatment in many patients with SVR; however, a significant difference was not observed due to the insufficient number of cases analyzed ( Figure S5 ). TbX21 has been shown to downregulate the expression of PD-1 in lymphocytes [ 19 ], while the expression of TbX21 was downregulated by the F protein produced by HCV [ 20 , 21 ]. F protein, a novel protein, is the product of an alternative reading frame (ARF) of the HCV polyprotein frame.…”

“…The HCV-derived F protein has been reported to contribute to the persistence of HCV infection, which may cause hepatic damage and, ultimately, carcinogenesis [ 21 , 28 , 29 ] and through the PD-1/PD-L1 pathway to induce T cell dysfunction: accelerating cell apoptosis and impairing T cell proliferation [ 30 ]. To clarify whether the F protein influences the expression of PD-1, our synthesized F protein was incubated with PBMCs collected from three representative cohorts.…”

Unconventional viral gene expression mechanisms as therapeutic targets

“…ARFs (such as overprinted ORFs) feature an overall low synonymous divergence [101][102][103] , and are therefore expected to be relatively constrained from accumulating mutations (as mutations in these regions are likely to disrupt more than one viral protein). Importantly, proteins encoded by ARFs have been shown to be abundantly synthesized during infections [104][105][106][107] and can be efficiently processed through class-I MHC processing pathways and induce cytotoxic T lymphocyte responses [108][109][110] .…”

A Proteomic Approach to Study the Biological Role of Hepatitis C Virus Protein Core+1/ARFP

“…Moreover, many positive-sense RNA viruses, which infect mammalian cells, present Alternative Reading Frame Proteins (ARFPs) in their genomes, which are also translated. The existence of such ARFPs poses some questions concerning their role during the infection since they do not directly affect the viral replication in the cell-based infection systems but may contribute to virus replication in vivo, during natural infection, thus representing virulent factors [ 13 ]. One such ARFP is an alternative open reading frame (ORF) overlapping the Core coding region in the +1 frame of genotype 1 and synthesizing another viral protein by a ribosomal frameshift mechanism within an A-rich area.…”