PubMed · 9643724
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E Cervoni. 1998-04-18. Hepatitis C.. https://doi.org/10.1016/s0140-6736(05)79162-5
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Hepatitis C virus (HCV) establishes persistent infection by rewiring host stress-response pathways. Chaperone-mediated autophagy (CMA) contributes to HCV replication, but it remains unclear whether HCV regulates lysosome-associated membrane protein 2 A (LAMP-2A), the rate-limiting receptor for CMA. Here, we examined LAMP-2A regulation in HCV-infected Huh-7.5 cells. HCV infection increased LAMP-2A promoter activity, mRNA, and protein abundance, indicating transcriptional upregulation. Among candidate stress-responsive transcription factors, nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1α (HIF-1α), and nuclear factor of activated T cells 1 (NFAT1) were elevated in infected cells. However, promoter mutagenesis identified NRF2 as the principal direct regulator. Mutation of the NRF2-responsive antioxidant response element markedly reduced basal and HCV-induced LAMP-2A promoter activity. Chromatin immunoprecipitation assays revealed NRF2 association with the LAMP-2A promoter, and HCV infection increased nuclear accumulation and Ser40 phosphorylation of NRF2. Functionally, shRNA-mediated knockdown of LAMP-2A reduced intracellular HCV RNA and protein levels. These findings identify an NRF2-LAMP-2A regulatory axis engaged during HCV infection and support a model in which HCV upregulates LAMP-2A to establish a cellular environment favorable for viral replication.
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UNLABELLED: CHRONIC INFECTION AND CIRRHOSIS: In France, the prevalence of hepatitis C virus (HCV) infection reaches an estimated 1% of the general population. Careful management is required since about 75% of all infected subjects will develop chronic liver disease with the risk of progression to cirrhosis. The major improvements in the efficacy of treatments developed over the last decade should help reduce the incidence of cirrhosis-related complications. PRACTICAL STEPS: A liver biopsy should be performed in all HCV-positive patients in order to study the histological impact. An antiviral treatment should be prescribed for patients free of decompensated cirrhosis or contraindications who have moderate to severe histological lesions. STANDARD TREATMENT: Alpha-interferon (3 MU three times a week) in combination with ribavirin (1000-1200 mg/d) should be given for 6 to 12 months. Resent publications have reported promising results with pegylated interferon which would be more effective and only require one injection per week. This new interferon, given in association with ribavirin, will undoubtedly shortly become the gold standard treatment for patients with chronic hepatitis C, particularly those infected with treatment-resistant geno-types.