Effects of the Ribavirin-Interferon Α Combination on Cultured Peripheral Blood Mononuclear Cells From Chronic Hepatitis C Patients

Martín, José Manuel García; Navas, Sonia; Quiroga, Juan Antonio; Pardo, Margarita; Carréño, Vicente

doi:10.1006/cyto.1997.0333

Cited by 67 publications

(60 citation statements)

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“…Although the molecular mechanisms involved in HCV inhibition by ribavirin are still poorly understood, there have been reports that ribavirin activates type 1 virus-specific cytotoxic T lymphocytes 37,38 and enhances the endogenous effects of IFN. 39 These pleiotropic effects of ribavirin-consistent with the beneficial results seen here on both phases of HCV dynamics in patients treated with a combination of ribavirin and IFN-are likely to be therapeutically relevant.…”

Section: Discussionsupporting

confidence: 80%

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

et al. 2001

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Hepatitis C virus (HCV) is known to infect and replicate within peripheral blood mononuclear cells (PBMC), thereby enabling the direct evaluation of antiviral mechanisms by analyzing HCV dynamics in PBMC. To address potential molecular differences associated with distinct antiviral regimens, we studied HCV dynamics in both serum and PBMC in 44 patients with HCV genotype 1b and high viral load who were randomly assigned to the following 4 different treatment groups: 1) combination therapy with 6 MU daily of interferon alfa 2b (IFN‐α2b) plus 800 mg of ribavirin; 2) monotherapy with 6 MU daily of IFN‐α2b; 3) monotherapy with twice‐daily intravenous administration with 3MU of IFN‐β; and 4) monotherapy with daily intravenous administration with 6 MU of IFN‐β. HCV‐RNA levels were measured serially using highly sensitive real‐time detection polymerase chain reaction (PCR). HCV dynamics in both the serum and PBMC showed a “biphasic” pattern. The exponential decay slopes of the second phase were significantly higher in the combination or twice‐daily dosing regimen groups compared with groups 2 or 4 (0.10 ± 0.08 vs. 0.02 ± 0.09 or 0.16 ± 0.09 vs. 0.02 ± 0.04 day−1; P < .05 or P < .0005, respectively). Moreover, the viral half‐lives in the second phase were significantly shorter in these groups (73.2 ± 42.5 vs. 240.1 ± 120.7 or 56.0 ± 44.6 vs. 361.6 ± 293.5 hours; P < .05 or P < .05, respectively). Additionally, the slope of HCV decline in PBMC tended to be higher in the combination regimens, as compared with monotherapy. Taken together, our data on HCV dynamics provide molecular insight into utilization of combination or twice‐daily dosing regimens to increase rates of sustained viral eradication of HCV.

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Section: Discussionsupporting

confidence: 80%

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

et al. 2001

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“…Furthermore, other reports support the concept that low doses of ribavirin can influence intracellular signal transduction. Thus, ribavirin promotes a shift toward a Th1 cytokine profile at doses between 1 and 10 M (22,26,35) and ribavirin at 20 M was able to induce mediator release from mast cells (21). In summary, our data demonstrate that the antiviral substances IFN and ribavirin are able to induce apoptosis and to sensitize for apoptosis mediated by the death receptor CD95.…”

Section: Discussionmentioning

confidence: 99%

Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

Schlosser¹,

Schüler²,

Berg³

et al. 2003

Antimicrob Agents Chemother

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The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

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“…Another study (Rigopoulou et al, 2000) demonstrated that ribavirin at 2 and 10 µM augmented HCV-specific T-cell reactivity in a proportion of patients with chronic hepatitis C. This effect was associated with an increase in IFN-γ and a decrease in IL-10 mRNA expression per cell. Martin et al (1998) …”

Section: Il-mentioning

confidence: 99%

Mechanisms of Action of Ribavirin in Antiviral Therapies

Tam¹,

Lau²,

Hong³

2001

Antivir Chem Chemother

113

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Although ribavirin was originally synthesized over 30 years ago and has been used to treat viral infections as monotherapy (respiratory syncytial virus and Lassa fever virus) or with interferon-α (IFN-α) as combination therapy (hepatitis C virus), the precise mechanism of its therapeutic activities remains controversial. In this review we focus on two main biological properties of ribavirin: its indirect and direct antiviral activities (with particular emphasis on its efficacy against chronic hepatitis C infection). Each property could individually or collectively account for its clinical efficacy against viral infections. First, with emphasis on the evidence for indirect activities of ribavirin, we will review the clinical observations that suggest that the immunomodulatory properties of ribavirin can in part account for its antiviral activities in vivo. We will then describe the mode of ribavirin's direct antiviral activities. These direct activities can be ascribed to several possible mechanisms, including the recently described activity as an RNA mutagen, a property that may be important in driving a rapidly mutating RNA virus over the threshold to 'error catastrophe'.

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Effects of the Ribavirin-Interferon Α Combination on Cultured Peripheral Blood Mononuclear Cells From Chronic Hepatitis C Patients

Cited by 67 publications

References 0 publications

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

Mechanisms of Action of Ribavirin in Antiviral Therapies

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