Hepatitis-C-Virus - Viruskinetik und Resistenzmechanismen

Zusammenfassung

Während der ersten Wochen einer auf Interferon basierenden Behandlung der chronischen Hepatitis-C-Virusinfektion kann üblicherweise ein biphasischer Abfall der Viruslast beobachtet werden. Die mathematisch-statistische Auswertung der Viruskinetik ermöglicht die Schätzung von individuellen kinetischen Raten, insbesondere der Verlustrate infizierter Zellen, der Abbaurate von freiem Virus sowie von einem Effizienzfaktor zur Hemmung der Virusproduktion. Die Analyse mathematischer Viruskinetikmodelle erlaubt Rückschlüsse auf die einer Therapie zugrunde liegenden Mechanismen. Ein effizientes bzw. fehlendes virologisches Therapieansprechen spiegelt sich außerdem typischerweise in guten bzw. schlechten kinetischen Parametern wider. Dies gilt für einzelne Patienten, aber auch für generelle Unterschiede im Rahmen der bekannten Genotypabhängigkeit des Therapieansprechens. Die Ursachen für ein vorhandenes oder fehlendes virologisches Therapieansprechen auf eine interferonbasierte Therapie bei einzelnen Patienten sind jedoch nicht bekannt. Neben wirts- und therapiespezifischen Ursachen wird vermutet, dass das HCV über spezifische Interferonresistenzmechanismen verfügt. Bisher wurden drei HCV-Proteine durch In-vitro-Untersuchungen in einen direkten Zusammenhang mit solchen Interferonresistenzmechanismen gebracht: das Hüllprotein (E)2 sowie die nichtstrukturellen Proteine (NS)3/4A und 5A. Spezifische Mutationen im Bereich der vermuteten Interaktionsstellen zur Vermittlung von Resistenzmechanismen in Korrelation mit dem virologischen Ansprechen auf eine interferonbasierte Therapie konnten dabei auf HCV-Isolaten von Patienten für das E2- (HVR2, CD81-Bindungsregion, PePHD) und NS3/4A-Protein nicht nachgewiesen werden. Im Bereich des NS5A-Proteins gibt es Hinweise für eine Bedeutung von Mutationen im Bereich einer Interferonsensitivität determinierenden Region (ISDR) bzw. des gesamten NS5A-Proteins bei HCV-1a/b-Isolaten.

Abstract

Typically, a biphasic decay of viremia can be observed during the first few weeks of interferon-based treatment in patients with chronic hepatitis C. The mathematical and statistical analysis of viral kinetics enables the estimation of individual kinetic parameters. Especially, the infected cell loss, the degradation rate of free virus, and an efficiency factor on blocking viral production can be estimated. Furthermore, mathematical models of viral kinetics have the potential to reveal mechanisms of antiviral therapy. The lower sustained virologic response rates in several patient populations are reflected by impaired kinetic parameters. Besides host-specific and treatment-related differences, especially hepatitis C virus genotype strongly correlates with initial and long-term virologic responses. Reasons for virologic response or non-response to interferon-based therapy for individual patients are unknown. Beside host- and treatment-related causes it is assumed that HCV is able to specifically evade the antiviral actions of interferon. So far, three HCV proteins [envelope (E)2, non-structural (NS) protein 3/4A, and NS5A protein] have been associated with interferon resistance mechanisms. However, within the E2 (HVR2, CD81 binding domains, PePHD) and NS3/4A proteins no specific mutations in correlation with virologic response to interferon-based antiviral therapy were observed. For the NS5A protein, mutations within the interferon sensitivity determining region (ISDR) and the complete NS5A protein may be of importance for virologic treatment response in patients infected with genotype HCV-1a/b isolates.

Schlüsselwörter

E2 - Hepatitis C - Interferon-α - ISDR - Mutationen - NS3 - NS4A - NS5A - Resistenzmechanismen - Viruskinetik

Key words

E2 - hepatitis C - interferon-α - ISDR - Mutations - NS3 - NS4A - NS5A - resistance mechanism - viral kinetics

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