The J6JFH1 Strain of Hepatitis C Virus Infects Human B-Cells with Low Replication Efficacy

Nakai, Masato; Seya, Tsukasa; Matsumoto, Misako; Shimotohno, Kunitada; Sakamoto, Naoya; Aly, Hussein Hassan

doi:10.1089/vim.2013.0140

Cited by 6 publications

(5 citation statements)

References 53 publications

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“…Human hepatocytes-derived HepG2 and Huh7 cells were obtained from the ATCC and maintained in DMEM medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin [4, 44]. The HBV119 T23 is a human hepatocyte-derived cell line that constitutively produces the HBV virions [13]; the cells were cultured in the DMEM with the addition of hygromycin B to maintain the HBV genome-integrated cells.…”

Section: Methodsmentioning

confidence: 99%

Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBVin vitroandin vivo

et al. 2016

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Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR). Consistently, addition of IFN-α induced Isg20 and partially suppressed HBV replication in hepatocytes. Chasing HBV RNA, DNA and proteins by blotting indicated that ISG20 expression decreased HBV RNA and replicative DNA in HBV-transfected cells, which resulted in low HBs antigen production and virus titer. The exonuclease domains of ISG20 mainly participated in HBV-RNA decay. In vivo hydrodynamic injection, ISG20 was crucial for suppressing HBV replication without degrading host RNA in the liver. Taken together, ISG20 acts as an innate anti-HBV effector that selectively degrades HBV RNA and blocks replication of infectious HBV particles. ISG20 would be a critical effector for ameliorating chronic HBV infection in the IFN therapy.

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Section: Methodsmentioning

confidence: 99%

Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBVin vitroandin vivo

et al. 2016

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“…Until now, to the best of our knowledge, complete propagation of HCV in nonhepatic cells has been accomplished only either in cell lines that endogenously express some exchangeable apolipoproteins (75) or through the exogenous expression of at least one of them (59,76,77). Although extrahepatic propagation of HCV still remains a controversial issue, high levels of CAMP expression and possible propagation of HCV in PBMCs were previously reported (78)(79)(80). Our present results support the idea that low levels of HCV propagation might be feasible in nonhepatic cells and/or tissues expressing CAMP but not apolipoproteins, such as bone marrow or PBMCs, that could serve as a reservoir for HCV.…”

Section: Discussionmentioning

confidence: 99%

Human Cathelicidin Compensates for the Role of Apolipoproteins in Hepatitis C Virus Infectious Particle Formation

Puig-Basagoiti

Fukuhara

Tamura

et al. 2016

J Virol

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Exchangeable apolipoproteins (ApoA, -C, and -E) have been shown to redundantly participate in the formation of infectious hepatitis C virus (HCV) particles during the assembly process, although their precise role in the viral life cycle is not well understood. Recently, it was shown that the exogenous expression of only short sequences containing amphipathic ␣-helices from various apolipoproteins is sufficient to restore the formation of infectious HCV particles in ApoB and ApoE double-gene-knockout Huh7 (BE-KO) cells. In this study, through the expression of a small library of human secretory proteins containing amphipathic ␣-helix structures, we identified the human cathelicidin antimicrobial peptide (CAMP), the only known member of the cathelicidin family of antimicrobial peptides (AMPs) in humans and expressed mainly in bone marrow and leukocytes. We showed that CAMP is able to rescue HCV infectious particle formation in BE-KO cells. In addition, we revealed that the LL-37 domain in CAMP containing amphipathic ␣-helices is crucial for the compensation of infectivity in BE-KO cells, and the expression of CAMP in nonhepatic 293T cells expressing claudin 1 and microRNA miR-122 confers complete propagation of HCV. These results suggest the possibility of extrahepatic propagation of HCV in cells with low-level or no expression of apolipoproteins but expressing secretory proteins containing amphipathic ␣-helices such as CAMP. IMPORTANCEVarious exchangeable apolipoproteins play a pivotal role in the formation of infectious HCV during the assembly of viral particles, and amphipathic ␣-helix motifs in the apolipoproteins have been shown to be a key factor. To the best of our knowledge, we have identified for the first time the human cathelicidin CAMP as a cellular protein that can compensate for the role of apolipoproteins in the life cycle of HCV. We have also identified the domain in CAMP that contains amphipathic ␣-helices crucial for compensation and show that the expression of CAMP in nonhepatic cells expressing claudin 1 and miR-122 confers complete propagation of HCV. We speculate that low levels of HCV propagation might be possible in extrahepatic tissues expressing secretory proteins containing amphipathic ␣-helices without the expression of apolipoproteins. According to recent estimates, more than 160 million people worldwide are chronically infected with hepatitis C virus (HCV) (1), which causes liver-related pathologies that can result in life-threatening diseases such as cirrhosis and hepatocellular carcinoma (2). Chronic HCV infection is also associated with several extrahepatic manifestations, including immunological disorders such as cryoglobulinemia and B-cell non-Hodgkin lymphoma (3). A vaccine is not yet available, but recent advances in antiviral treatment, improving upon what was for many years the standard therapy of pegylated interferon alpha plus ribavirin, now include several direct-acting antivirals (DAAs) that have increased the rate of sustained virological response (SVR) up to 80 ...

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Section: Pathogenesis Of Hcv-associated Nhlmentioning

confidence: 99%

“…Despite HCV replication being less efficient in B lymphocytes than in hepatocyte line (Huh7) cells, their outcomes show that human B lymphocytes without other non-B cells can be infected with HCV. 69 Intracellular viral proteins have been demonstrated to potentially contribute to direct oncogenic transformation in several mouse models. For instance, following a latency period of between 180 and 600 days, mice with the combination of interferon regulatory factor-1 inactivation and persistent expression of HCV structural proteins, such as CN2, develop lymphoproliferative diseases.…”

Section: Direct Mechanisms: Oncogenic Effects Mediated By Intracellul...mentioning

confidence: 99%

Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies

Zhang¹,

Du²,

Li³

et al. 2023

J Clin Transl Hepatol

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Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.

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The J6JFH1 Strain of Hepatitis C Virus Infects Human B-Cells with Low Replication Efficacy

Cited by 6 publications

References 53 publications

Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBVin vitroandin vivo

Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBVin vitroandin vivo

Human Cathelicidin Compensates for the Role of Apolipoproteins in Hepatitis C Virus Infectious Particle Formation

Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies

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