Hepatitis Viruses Fe A. Bartolome, MD Department of Microbiology Our Lady of Fatima University

HEPATITIS A infectious hepatitis; Enterovirus 72 Picornavirus genus Heparnavirus/Hepatovirus naked, icosahedral symmetry positive sense, ssRNA virus with a VPg protein attached to 5” end replication similar to other Picornaviruses not cytolytic released by exocytosis

HEPATITIS A Characteristics: Stable to: acid (pH 1), solvents (ether, chloroform), detergents, salt/ground water, drying, temperature (40C – 560C) Inactivated by: chlorine treatment, formalin, UV radiation

HEPATITIS A Pathogenesis: MOT: fecal-oral  food (shellfish – clams, oysters, mussels); water; dirty hands Ingestion  oropharynx or epithelial lining of intestines  blood stream  liver (hepatocytes and Kupffer cells)  bile  stool Virus shedding: 2-3 wks before & 1 week after onset of jaundice or until antibody is detected Interferon – limits viral shedding NK cells & cytotoxic T cells  lysis of infected cells Antibody, complement, ADCC  induce immunopathology

HEPATITIS A Pathogenesis: MOT: fecal-oral  food (shellfish – clams, oysters, mussels); water; dirty hands Ingestion  oropharynx or epithelial lining of intestines  blood stream  liver (hepatocytes and Kupffer cells)  bile  stool Virus shedding: 2-3 wks before & 1 week after onset of jaundice or until antibody is detected Interferon – limits viral shedding NK cells & cytotoxic T cells  lysis of infected cells Antibody, complement, ADCC  induce immunopathology

HEPATITIS A Epidemiology: 90% of infected children & 20-25% of infected adults with inapparent but productive infections HAV viremia transient  blood-borne transmission rare

HEPATITIS A Clinical Syndromes: Children: mild infection, usually asymptomatic Adults: abrupt onset of symptoms viral shedding precedes onset of symptoms complete recovery in 99% fulminant hepatitis: 1-3 persons/1000 with 80% mortality immune complex-related symptoms rare

HEPATITIS A Laboratory Diagnosis: ELISA or radioimmunoassay (+) IgM anti-HAV  acute infection  fecal shedding decreases as IgM titer increases (+) IgG anti-HAV  resolution, past infection Prophylaxis: immune serum globulin < 2 wks after exposure

HEPATITIS B serum hepatitis Hepadnavirus infects liver, kidneys and pancreas  humans and chimpanzees 15% of population infected during birth or childhood small, enveloped circular, partly ds DNA virus mature virion  Dane particle

HEPATITIS B Important proteins: DNA polymerase – with reverse transcriptase & ribonuclease H activity HBcAg – core antigen; surrounds polymerase; T cell antigens HBeAg – minor component of virion; primarily secreted into serum HBsAg – surface antigen; Australia antigen HBx – transcriptional transactivator; promote viral replication; protein kinase

HEPATITIS B HBsAg with 3 glycoproteins encoded by same gene but translated from different AUG start codons S (gp27) – contained in M glycoprotein; major component of HBsAg M (gp36) – contained in the L glycoprotein L (gp42) – essential for virion assembly

HEPATITIS B Replication unique: With distinctly defined tropism for liver Small genome  economy in transcription and translation Replicates through an RNA intermediate Binds to human serum albumin  target the virus to the liver Cell penetration  partial DNA strand converted to complete dsDNA  nucleus

HEPATITIS B two phases of hepatocyte infection: Proliferative phase HBV DNA present in episomal form Viral HBsAg & HBcAg + MHC class I molecules  activation of CD8+ T cells  (+) hepatocyte destruction Integrative phase For hepatocytes not destroyed by immune system  viral DNA incorporated into host genome

HEPATITIS B (+) HBsAg and HBeAg in blood  on-going active infection MOT: Blood & other body fluids – semen, saliva, milk, vaginal secretions, amniotic fluid Sexual contact Perinatal – passage through birth canal Intracellular accumulation of filamentous forms of HBsAg  responsible for characteristic ground glass cytopathology

HEPATITIS B CMI + inflammation  responsible for causing symptoms; eliminate infected hepatocytes Immune complexes between HBsAg and anti-HBs  (+) type III HS reaction  vasculitis, arthralgia, rash, renal damage Infants & young children  immarture CMI  less ability to resolve infection  90% chronic carriers

Prevent spread & disease HEPATITIS B Spread of Hepatitis B MOT Blood Liver Prevent spread & disease Ab HBsAg Symptoms, resolution Viremia Immune complex Type III HS CMI

Extrahepatic disease: PAN, GN HEPATITIS B Clinical outcomes: Acute Hepatitis B Resolution Fulminant HBsAg+ > 6 months Asymptomatic carrier state Chronic persistent hepatitis Chronic active hepatitis Extrahepatic disease: PAN, GN Cirrhosis HCC 90% 9% 1% 50%

HEPATITIS B Laboratory: Detection of HBeAg is the best correlate to the presence of infectious virus Chronic infection  continued finding of HBeAg, HBsAg or both without detectable antibodies

HEPATITIS B Interpretation of Serologic Markers of HBV Infection Serologic reactivity Pre- symptoms Early Acute Acute Chronic Late acute Resolved Vacci-nated Anti-HBc Anti-HBe Anti-HBs HBeAg HBsAg Infectious virus - + +/-

HEPATITIS C NANB post-transfusion hepatitis Flavivirus genus Hepacivirus Enveloped, ss positive sense RNA virus 5’ end encodes nucleocapsid core protein  highly conserved Envelope proteins  E1 and E2 Hypervariable regions (HVR1 & 2)  present in E2 sequence Non-structural proteins (e.g. NS5B  viral RNA-dependent RNA polymerase)  with poor fidelity

HEPATITIS C Infects only humans and chimpanzees Binds to cells with CD81 surface receptors OR coats itself with LDL or VLDL & uses their receptors for uptake into hepatocytes Inhibit apoptosis & IFN- by binding to TNFR and protein kinase R (PKR)  prevent death of host cell and promote persistent infection CMI  production of tissue damage Antibody not protective

HEPATITIS C Remains cell-associated MOT: Parenteral - >90% of HIV (+) individuals infected with HCV Secretions Sexual Perinatal (6%) PERSISTENT INFECTION AND CHRONIC HEPATITIS ARE THE HALLMARKS!

HEPATITIS C Outcomes: HCV Acute infection Recovery & clearance Persistent infection Chronic hepatitis Liver failure Cirrhosis HCC

HEPATITIS C Laboratory: (+) anti-HCV antibodies (50-70%) in symptomatic acute infection HCV RNA persists despite presence of neutralizing antibodies (90%) Episodic elevation of serum aminotransferases Treatment: IFN- alone or with ribavirin – only known treatment

HEPATITIS D Delta hepatitis; viroid-like Replication defective  viral parasite Enveloped, circular RNA virus  surrounded by delta antigen core  surrounded by HBsAg-containing envelope Unusual transcription and replication process Host cell RNA pol II  makes RNA copy  replicates genome  makes mRNA  form a ribozyme  cleave RNA circle  form mRNA

HEPATITIS D MOT similar to HBV Replicate and cause disease only in people with active HBV infection  results in cytotoxicity and liver damage With direct cytopathic effect

Chronic HBV/HDV hepatitis HEPATITIS D Clinical outcomes: Co-infection HDV + HBV Healthy individual 3-4% 90% rare Fulminant hepatitis Recovery w/ immunity Chronic HBV/HDV hepatitis Death Cirrhosis

Chronic HBV/HDV hepatitis HEPATITIS D Clinical outcomes: Superinfection HDV HBV carrier Fulminant hepatitis Acute, severe disease Chronic HBV/HDV hepatitis Cirrhosis Death 10-15% 80% 7-10% Recovery

HEPATITIS E Enteric or epidemic NANB hepatitis MOT: fecal-oral Resembles Calicivirus or Norwalk agent in size and structure  non-enveloped, ssRNA virus Symptoms and course similar to HAV Causes only acute disease Poor response to serum IgG Infection serious in pregnant women  mortality approx. 20%

HEPATITIS G Flavivirus similar to HCV MOT: contaminated blood or blood products; possibly sexual In 75% of infection  HGV cleared from plasma; 25% become chronic Site of replication: mononuclear cells  not hepatotropic Does not cause elevation in serum aminotransferases With protective effect on patients co-infected with HIV  inhibit HIV replication in cultures of peripheral blood mononuclear cells