Lymphotropic HCV strain can infect human primary naïve CD4+ cells and affect their proliferation and IFN-γ secretion activity

Kondo, Yasuteru; Ueno, Yoshiyuki; Kakazu, Eiji; Kobayashi, Koju; Shiina, Masaaki; Tamai, Keiichi; Machida, Keigo; Inoue, Jun; Wakui, Yuta; Fukushima, Koji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru

doi:10.1007/s00535-010-0297-2

Cited by 34 publications

(44 citation statements)

References 33 publications

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“…However, the antiviral activity of 25(OH) vitamin D3 is not so remarkable. Moreover, the system of HCV replication in that study did not include the immune cells that are important for the control of HCV replication [32]–[35].…”

Section: Discussionmentioning

confidence: 99%

1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response during Peg-IFN/RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial

et al. 2013

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Objective1,25(OH)2 vitamin D3 can affect immune cells. However, the mechanism responsible for the favorable effects of 1(OH) vitamin D3, which becomes 1,25(OH)2 vitamin D3 in the liver, is not clear. The aim of this study is to analyze the immunological response of 1(OH) vitamin D3 supplementation in CH-C patients.DesignForty-two CH-C patients were treated with 1(OH) vitamin D3/Peg-IFNα/RBV. Forty-two case-matched controls were treated with Peg-IFNα/RBV. The expression of Interferon-stimulated genes (ISGs)-mRNA in the liver biopsy samples and JFH-1 replicating Huh-7 cells were quantified by real-time PCR. Ten kinds of cytokines in the plasma were quantified during treatment by using a suspension beads array. A trans-well co-culture system with peripheral blood mononuclear cells (PBMCs) and Huh-7 cells was used to analyze the effect of 1(OH) vitamin D3. The activities of the Th1 response were compared between subjects treated with 1(OH) vitamin D3/Peg-IFN/RBV and those treated with Peg-IFN/RBV therapy alone.Results1(OH) vitamin D3/Peg-IFN/RBV treatment could induce rapid viral reduction, especially in IL28B T/T polymorphism. Several kinds of cytokines including IP-10 were significantly decreased after 4 weeks of 1(OH) vitamin D3 treatment (p<0.05). Th1 responses in the subjects treated with 1(OH) vitamin D3/Peg-IFN/RBV were significantly higher than those treated with Peg-IFN/RBV at 12 weeks after Peg-IFN/RBV therapy (p<0.05). The expression of ISGs in the patient’s liver biopsy samples was significantly lower than in those treated without 1(OH) vitamin D3 (p<0.05).Conclusion1(OH) vitamin D3 could improve the sensitivity of Peg-IFN/RBV therapy on HCV-infected hepatocytes by reducing the IP-10 production from PBMCs and ISGs expression in the liver.

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Section: Discussionmentioning

confidence: 99%

1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response during Peg-IFN/RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial

et al. 2013

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“…Although the capacity of culture-produced HCV from a different genotype (2a) to infect PBMC has been challenged [52], it has also been shown that HCV from the same genotype as the one used in this manuscript (1a) [51] infects primary CD4+ T cells. HCV-Core could also enter CD4+ T cells as it has previously been suggested [23], [40], [53] and data showing that HCV-core protein is present in hepatocytes[54], non-parenchymal liver cells including lymphocytes [55] and in the serum of infected patients [56], together with data showing that it can enter hepatoma cell lines [57] further reinforces such an hypothesis.…”

Section: Introductionmentioning

confidence: 99%

CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

et al. 2014

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Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.

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“…Our in vitro clearance and rebound study was a first step toward demonstrating that PSI-352938 was capable of clearing HCV RNA. It is possible that the outcome from an in vivo situation could be different from the results of in vitro studies, especially since HCV could infect organs other than the liver, such as the lymphatic system (24).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine

Lam¹,

Espiritu²,

Murakami³

et al. 2011

Antimicrob Agents Chemother

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PSI-352938 is a novel cyclic phosphate prodrug of ␤-D-2-deoxy-2-␣-fluoro-2-␤-C-methylguanosine 5-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 M, respectively. The active 5-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. Hepatitis C virus (HCV), an important member of the Flaviviridae family of viruses, is a major health problem affecting approximately 170 million people worldwide. In the United States, where it is the leading cause of liver transplantation, nearly 2% of the U.S. population are HCV carriers (2). The current standard of care (SOC), which consists of pegylated alpha interferon (IFN-␣) and ribavirin, results in only about a 50% sustained virological response in patients infected with genotype 1 HCV, the predominant genotype in the United States and Europe (13, 18). The limited cure rate and potential side effects associated with interferon and ribavirin (10, 11) prompted the development of direct-acting antiviral agents (DAAs) in order to improve clinical efficacy and tolerability.Among the DAAs currently in clinical development, nucleoside/nucleotide analogs as inhibitors of HCV replication have the advantage of broad genotype coverage and a high barrier to resistance (14). The active 5Ј-triphosphates of nucleoside/ nucleotide analogs target the HCV NS5B RNA-dependent RNA polymerase (Pol) by serving as alternative substrate inhibitors during RNA synthesis (6). Both of the two resistance mutations identified so far, S96T and S282T, are highly conserved residues and unfit for HCV replicon replication (33). Among the nucleoside/nucleotide analogs, RG7128 (the prodrug of PSI-6130, ␤-D-2Ј-fluoro-2Ј-C-methylcytidine) is the most advanced anti-HCV nucleoside and is currently in phase IIb clinical studies. So far, results from the clinical studies showed that RG7128 is generally safe and effective in reducing the viral loads for genotype 1, 2, 3, and 4 HCV-infected patients when it is combined with SOC, with no resistance-related breakthrough (16,21,27,37).More recently, we reported results of in vitro studies characterizing PSI-7851 and PSI-7977 (the single Sp isomer of PSI-7851), phosphoramidate prodrugs of ␤-D-2Ј-fluoro-2Ј-Cmethyluridine 5Ј-monophosphate (30,45,48). While RG7128 was designed to improve the pharmacokinetic profile of PSI-6130, PSI-7851 and PSI-7977 were synthesized to bypass the nonproductive first phosphorylation step, as the corresponding nucleoside analog was incapable of being converted to the monophosphate form. In a 3-day phase I monotherapy study, a 1.95-log vira...

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Lymphotropic HCV strain can infect human primary naïve CD4+ cells and affect their proliferation and IFN-γ secretion activity

Cited by 34 publications

References 33 publications

1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response during Peg-IFN/RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial

1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response during Peg-IFN/RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial

CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine

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