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Suchttherapie 2002; 3(Suppl. 1): S37-S44
DOI: 10.1055/s-2002-32765
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© Georg Thieme Verlag Stuttgart · New York

Virologische und immunologische Grundlagen der Therapie der chronischen HCV-Infektion

Virologic and Immunologic Backgrounds for the Treatment of Chronic Hepatitis C Virus InfectionChristoph Sarrazin, Stefan Zeuzem
  • 1Medizinische Klinik II, Johann Wolfgang Goethe-Universität Frankfurt am Main
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Publication History

Publication Date:
11 July 2002 (online)

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Zusammenfassung

Das Hepatitis-C-Virus (HCV) ist ein hepatotropes Einzel-(+)Strang RNA-Virus, das häufig zu einer chronischen Leberentzündung führt und mit dem Risiko der Entwicklung einer Leberzirrhose und eines Leberzellkarzinoms assoziiert ist. Das HCV kodiert für drei strukturelle (Kapsid, Hüllprotein 1 und 2) und 6 nicht strukturelle Proteine (NS2, 3, 4A, 4B, 5A und 5B). Bei der HCV-Infektion werden Antikörper gegen eine hypervariable Region des Hüllproteins 2 ausgebildet, die vermutlich neutralisierende Eigenschaften haben. Bei der T-Zellantwort scheint die CD4-positive, von TH1-Zellen getragene Immunantwort von besonderer Bedeutung für den Verlauf der akuten Infektion und einer antiviralen Therapie zu sein. Die Therapie mit Interferon-alpha wird über antivirale, antiproliferative und immunmodulatorische Effekte vermittelt. Die antiviralen Wirkungen des Nukleosidanalogons Ribavirin gegenüber dem HCV sind noch nicht vollständig verstanden. Das Hüllprotein 2 (E2) sowie das NS5A-Protein scheinen für Therapieresistenzmechanismen des HCV verantwortlich zu sein. Bei In-vitro-Untersuchungen fand sich eine Hemmung der Interferon-alpha induzierten Doppelstrang-RNA-abhängigen Proteinkinase (PKR) durch Bindung an eine spezifische Region des E2- und NS5A-Proteins. Klinisch sind Mutationen im Bereich des NS5A-, nicht aber des E2-Proteins mit dem Ansprechen auf eine antivirale Therapie mit Interferon-alpha und Ribavirin korreliert.

Abstract

Hepatitis C virus (HCV) is a positive single-strand RNA virus leading to chronic hepatitis with subsequent development of cirrhosis and its sequelae. HCV is coding for 3 structural (core, envelope 1 and 2) and 6 non-structural proteins (NS2, 3, 4A, 4B, 5A and 5B). Antibodies developing against the hypervariable region 1 within envelope 2 protein have neutralising effects. T cell response of CD4 positive TH1-cells is important for recovery from acute HCV infection as well as for response to antiviral therapy. Treatment of chronic HCV infection with interferon-alpha is mediated through antiviral, antiproliferative and immunomodulatory effects. Antiviral effects of the nucleoside analog ribavirin are not yet fully understood. Envelope protein 2 (E2) as well as the NS5A protein seem to be involved in interferon-alpha resistance mechanisms of HCV. Interferon-alpha induced double-strand RNA dependent proteinkinase (PKR) is inhibited in vitro due to specific binding of E2 and NS5A protein. Clinically mutations within the NS5A protein but not within the E2 protein are positively correlated with response to interferon-alpha and ribavirin combination therapy.

Schlüsselwörter

Hepatitis-C-Virus - Molekularbiologie - Interferon-alpha - Ribavirin - Therapieresistenz

Key words

Hepatitis C Virus - Molecular Biology - Interferon-Alpha - Ribavirin - Treatment Resistance Mechanism

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Dr. med. Christoph Sarrazin

Johann Wolfgang Goethe-Universität Frankfurt am Main, Medizinische Klinik II

Theodor-Stern-Kai 7

60590 Frankfurt am Main

Email: sarrazin@em.uni-frankfurt.de