Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections

Abstract

Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.

Optimal Control of Drug Therapy in a Hepatitis B Model

“…The removal of the hepatitis B e-antigen is associated with immunological factors, such as removal of the tolerant status of the hepatitis B-specific T cells [36]. Such effects have been demonstrated by interferon therapy, which leads to improved immune function, sustained response rates with combination therapy and improved overall prognosis [37]. These drugs have limitations, such as side effects, the use of injection and poor response in patients with compromised liver function.…”

“…The contributions of interferon-α are complex, with both direct antiviral and immunomodulatory effects. Here, we consider three effects of IFN-α: enhancement of effector cell killing rates, reduction of viral production rate and the delay of effector cell programmed death [36,37]. We model this by changing rates µ, π and d to µ 1 a 3 ), respectively.…”

Immunválasz és oxidatív stressz hepatitis C-vírus-infekcióban

“…Az innate válaszban az első reakció a TLR-3 receptoron keresztül indukálódó IFN-β-termelés a hepatocytákban. NK-sejtek direkt citotoxikus potenciával is bírnak, a célsejteket minden előzetes szenzitizálás nélkül támadják [6,7,8].…”

“…A CTLA-4 inhibitoros receptor expressziója is fokozódik. Amíg akut HCV-infekcióban az IFN-α helyreállítja a káro-sodott T-sejt-funkciót, krónikus fertőzésben ez nem észlelhető, azonban a direkt ható antivirális szerek ilyenkor is hatásosak a T-sejtes immunfunkció helyreállításában [4,8]. -Elmenekülés (escape) a T-sejt-felismerés elől, a kvázi-speciesek keletkezése révén.…”

“…HCV hatására a dendritikus sejtekben (DC) az IL-12-képzés csökkenését, az IL-10 fokozott képzését is közölték. -A HCV E2 protein és az NK-sejt CD81 keresztkötése gátolja az NK-funkciót (IFN-képzést, TNF-α-szekréciót) [4,7,8]. -Az IFN-λ-4-expressziót kontrolláló gén delta-G allélje a HCV csökkent spontán clearance-ével társul, és szoros kapcsolatban van a hepaticus interferonstimulált gén (ISG) fokozott expressziójával és a P/R kezelésre való rossz válaszkészséggel [9].…”