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Host proteins associated with Hepatitis C virus encoded NS4A.

ABSTRACT: Virus-associated cancers account for more than 12 % of all the cancers. Hepatitis C virus (HCV) infects nearly 3 % of the population worldwide and has emerged as a major causative agent of liver disease with a big impact on public health. The HCV non-structural protein NS4A is a 54-amino-acid polypeptide that serves as an essential co-factor for the NS3 serine protease. We report here on a proteomic study to identify cellular proteins associated with NS4A. The results of this study show an association of three host cellular proteins with NS4A including two novel NS4A interacting partners. Our data provide evidence for complex involving NS4A with previously unreported cellular proteins including housekeeping protein GAPDH, and PI3P-5 K which is involved in cellular protein trafficking to nucleus. These novel associations add to the diversity of NS4A functions in relation to the virus infection and subsequent pathogenesis.

SUBMITTER: Dabral P

PROVIDER: S-EPMC4262306 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Host proteins associated with Hepatitis C virus encoded NS4A.

Dabral Prerna P Khera Lohit L Kaul Rajeev R

Virusdisease 20141112 4

Virus-associated cancers account for more than 12 % of all the cancers. Hepatitis C virus (HCV) infects nearly 3 % of the population worldwide and has emerged as a major causative agent of liver disease with a big impact on public health. The HCV non-structural protein NS4A is a 54-amino-acid polypeptide that serves as an essential co-factor for the NS3 serine protease. We report here on a proteomic study to identify cellular proteins associated with NS4A. The results of this study show an assoc ...[more]

PMID: 25674628

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Project description:UnlabelledA lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection.ImportanceHCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection, but ethical considerations have restricted their utility in biomedical research. GB virus B (GBV-B) is a flavivirus related to HCV. It can infect common marmosets, a New World small primate, and induces viral hepatitis similar to HCV infection in humans. To minimize differences between GBV-B and HCV, we generated HCV NS2 to -4A/GBV-B chimeric viruses and established a chimera-infected marmoset model. HCV NS2 to -4A chimera-infected marmosets provide a small-animal model for evaluating novel antiviral drugs targeting HCV NS3-NS4A protease and T-cell-based HCV vaccines.

Dataset Information

Host proteins associated with Hepatitis C virus encoded NS4A.

Publications

Host proteins associated with Hepatitis C virus encoded NS4A.

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