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

2. 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

3. 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

4. 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

5. 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

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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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%

18. 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

19. 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 - +
+/-

20. 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

21. 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

22. 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!

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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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%

30. 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