Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus.
OBJECTIVE
An understanding of ribavirin's beneficial effects on treatment outcome in chronic hepatitis C (CH-C) may help to develop new treatment approaches. Here we investigated whether ribavirin directly affects HCV-specific reactivity of CD4+T-lymphocytes from patients with CH-C.


METHODS
Peripheral blood mononuclear cells from forty HCV RNA positive patients were cultured ex vivo with HCV core, NS3, NS4 alone, and with different concentrations of ribavirin. Virus-specific CD4+ T-cell reactivity was analysed by a proliferation assay; quantitation of cytokine (interferon-gamma, IL-10, IL-5, IL-12p35, IL-12p40) mRNA levels; measurement of interferon-gamma and IL-10 production (by ELISA) and enumeration of interferon-gamma and IL-10 producing T-cells by Elispot assays.


RESULTS
At 2-5 microM ribavirin induced de novo or enhanced T-cell proliferation to HCV antigens in a proportion of patients. Increased T-cell proliferation was associated with decreased IL-10 production in response to HCV core and reduced frequency of IL-10 producing CD4+ T-cells, while interferon-gamma levels remained unchanged. At 20 microM ribavirin markedly suppressed T-cell proliferation, and interferon-gamma mRNA expression to HCV antigens.


CONCLUSIONS
Ribavirin, at clinically achievable plasma levels, modulates directly the T-cell responses to HCV antigens in some CH-C patients. Suppression of IL-10 production may represent a useful strategy to induce/augment T-cell reactivity to HCV.
Rigopoulou
Eirini I
EI
Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, UK.
Abbott
William G H
WG
Williams
Roger
R
Naoumov
Nikolai V
NV
D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D016174:Hepacivirus / Q000187:drug effects*; D018936:Hepatitis C Antigens / Q000097:blood; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D014758:Viral Core Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D016207:Cytokines; D018936:Hepatitis C Antigens; D007371:Interferon-gamma; D016753:Interleukin-10; D010446:Peptide Fragments; D012333:RNA, Messenger; D012367:RNA, Viral; D012254:Ribavirin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C516958:core protein (1-98), hepatitis C virus