Hepatitis virus immunity Mar 9 2005 Rehermann and Nascimbeni review Crispe review HBV HCV infection outcomes Both viruses cause immune mediated active and chronic hepatitis HBV Vertical transmission chronic hepatitis Adult infection protective immunity HCV Adult infection 60 80 chronic hepatitis Clinical features Feature Hepatitis B Hepatitis C Worldwide 350 million infected 170 million infected United States 1 million infected 4 million infected Vertical transmission Mother to neonate Chronic hepatitis Rare Horizontal transmission IV drug use parenteral sexual Recovery IV drug use parenteral sexual Chronic hepatitis Vaccine Yes No Molecular virology Feature HBV HCV Structure 42 nm enveloped partially dsDNA 50 nm enveloped stranded RNA Family Hepadnaviridae Flaviviridae Receptor Unknown Includes CD81 Mutation rate Low 10 5 base High 10 3 base Genotypes 8 low divergence 6 with 50 subtypes Image removed for copyright reasons Source Figure 1 in Rehermann B and M Nascimbeni Immunology of hepatitis B virus and hepatitis C virus infection Nature Review Immunology 5 no 3 2005 HBV molecular virology Relaxed circular 3 2 kb genome Full length negative strand 5 viral RT Partial positive strand 5 oligoribonucleotide cccDNA template for transcription of 4 viral RNAs in nucleus Exported to cytoplasm and translated Longest RNA also serves as template for HBV replication in nucleocapsids in the cytoplasm Some DNA and nucleocapsids return to nucleus Others bud into ER are secreted via golgi HCV molecular virology ssRNA 10K nucleotides Single long ORF flanked by 2 UTRs Replicates in the cytoplasm Translation initiated by internal ribosomal entry site in 5 UTR Polyprotein processed into structural and non structural proteins Combine with viral RNA to form membraneassociated replication complexes Nucleocapsids bud into cytoplasmic vesicles Acute HBV infection in adults HBV DNA is detectable in circulation within 1 month of infection Remains at a low level 102 104 genome equivalents ml for up to 6 weeks HBeAg and HBsAg reach peak levels HBcAg specific IgM appears early and IgG persists for life regardless of outcome T cell mediated liver damage begins to be apparent 10 15 weeks after infection Most viral DNA is cleared by this time Acute HBV infection in adults 90 of acutely infected adults resolve all clinical signs develop HBeAg and HBsAgspecific antibodies clear HBeAg and HBsAg from circulation and maintain lifelong protective immunity Despite complete clinical recovery trace amounts of HBV DNA persist and are controlled by humoral and cellular immune responses Acute HCV infection in adults HCV reaches high levels in serum within 1 week after infection Cellular immune response takes 1 month and humoral immune response 2 months Clinical signs associated with T cell mediated liver damage are rare Liver enzymes indicating tissue damage are detectable 8 12 weeks after infection Viral RNA declines Development of HCV specific Ig is variable Acute HCV infection in adults HCV specific antibodies do not indicate the outcome of infection Most individuals develop chronic hepatitis with relatively stable viral titers 2 3 logs below that in the acute phase Only a small proportion of patients recover and test negative for viral RNA Whether complete eradication occurs is controversial Protective immunity to HBV Clinical recovery is associated with lifelong protective immunity Trace amounts of virus persist Reactivation with immunosuppression Transmission via organ transplantation Trace virus may maintain immune response Controversy regarding need to boost to maintain vaccine induced HBsAg specific immunity Protective immunity to HCV Recovery is associated with HCV specific T cells B cell responses are variable and may not persist Whether HCV is completely eradiated or trace amounts remain is controversial Protective immunity is not believed to be completely protective or lifelong But data in humans are limited Liver tolerance Portal blood is rich in bacterial products and food derived antigens Malaria HBV and HCV all persist Allogeneic liver grafts can be established and maintained without immunosuppression Local presentation of Ag causes T cell inactivation tolerance and apoptosis Immune cells in the liver Resident macrophages Kupffer cells Can sometimes be effective APCs Also seem to be involved in tolerance Intrahepatic lymphocytes CD8 CD4 NK and NKT populations are enriched Portal vein Arteriole Dendritic cell Bile duct Kupffer cell Lymphocyte Sinusoid Plate of hepatocytes Central vein Kupffer cell Hepatic Sinusoid Space of Disse PC Immature DC LSEC Blood from portal vein Hepatocyte Lymph drains from space of Disse and enters lymphatic capillaries in the portal area Blood to central vein Figure by MIT OCW NK cells in the liver Infected hepatocyte Hepatic sinusoid Kupffer cell NK CCL3 IL 12 IL 18 T cell Activated NK cell IFN NK LSEC isse IFN eo ac Sp CXCL9 fD T cell Important role in T cell recruitment In response to type 1 IFN Kupffer cells produce CCL3 MIP 1 Once activated by Kupffer cell IL 12 produce IFN Induces other cells to secrete CXCL9 MIG Figure by MIT OCW DC trafficking in the liver CCR7 DC DC Hepatic sinusoid Lymphoid Tissue CCR5 pre DC CCR7 DC CCL3 Hepatocyte CCR1 CCR1 CCR5 Kupffer cell LSEC Space of Disse Also in response to Kupffer cell CCL3 immature DC respond via CCR1 Downregulate CCR1 and CCR5 upregulate CCR7 and become responsive to CCL21 Migrate to lymphoid aggregates in portal tracts and to LN Figure by MIT OCW T cell tolerance in the liver A B Space of Disse Space of Disse Partial activation G0 G1 no IL 2 Naive CD4 T cell IL 14 TReg Naive CD8 T cell IL 10 Kupffer cell Passive apoptosis IL 13 Phagocytosis Hepatic Sinusoid Hepatocyte LSEC Hepatocyte Figure by MIT OCW Hepatic Sinusoid Overcoming base line tolerance Infected hepatocyte IFN Hepatic sinusoid IL 12 CD4 T cell Hypothesis that type 1 IFN allows liver sinusoidal endothelial cells to produce IL 12 Promotes differentiation of Th1 cells IL 15 serves as a survival factor for CD8 T cells TH1 Pro inflammatory CD4 T cell CD8 T cell CD8 T cell Viable cell IL 15 LSEC Space of Disse Figure by MIT OCW