RESUMO
Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics.
Assuntos
Hepatite D/tratamento farmacológico , Hepatite D/virologia , Vírus Delta da Hepatite/fisiologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Genoma Viral , Glicoproteínas/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite D/imunologia , Vírus Delta da Hepatite/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunocompetência , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Simportadores/metabolismo , Transgenes , Viremia/tratamento farmacológico , Viremia/patologiaRESUMO
In order to document the incidence of hepatitis delta virus (HDV) replication markers and their relationship to HBV replication, 91 HBsAg chronic carriers were studied. Of these, 51 were anti-HD-positive (19 HBeAg-positive and 32 anti-HBe-positive). Liver HDAg was found in 75% of anti-HD-positive patients. Of the 19 patients who had anti-HD and HBeAg, 13 were HBV-DNA-positive. None of the anti-HBe patients were HBV-DNA-positive. No differences with respect to HBV-DNA concentration were observed between anti-HD-positive and -negative patients. Liver HDAg was detected with similar frequency in patients who were HBeAg- and HBV-DNA-positive (63.6%) and in those who were anti-HBe-positive (78.5%), with no statistically significant difference. HBcAg and HDAg were simultaneously detected in 36% of the anti-HD cases. Patients with anti-HD and HBV-DNA had the highest levels of transaminases (SGPT). Our results suggest that in certain patients HDV and HBV replication coexists without mutual inhibition.
