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:

1. DNA polymerase – with reverse transcriptase & ribonuclease H activity

2. HBcAg – core antigen; surrounds polymerase; T cell antigens

3. HBeAg – minor component of virion; primarily secreted into serum

4. HBsAg – surface antigen; Australia antigen

5. 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

1. S (gp27) – contained in M glycoprotein; major component of HBsAg

2. M (gp36) – contained in the L glycoprotein

3. L (gp42) – essential for virion assembly

HEPATITIS B

Replication unique:

1. With distinctly defined tropism for liver

2. Small genome economy in transcription and translation

3. 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:

1. Proliferative phase

HBV DNA present in episomal form

Viral HBsAg & HBcAg + MHC class I molecules activation of CD8+ T cells (+) hepatocyte destruction

2. 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:

1. Blood & other body fluids – semen, saliva, milk, vaginal secretions, amniotic fluid

2. Sexual contact

3. 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

HEPATITIS B

Spread of Hepatitis B

MOT Blood

Liver

Prevent spread & disease

Ab

Ab

HBsAg

Symptoms, resolution

Viremia

Immune complex

Type III HS

CMI

HEPATITIS B

Clinical outcomes:

Acute Hepatitis B

Resolution Fulminant

HBsAg+ > 6 months

Resolution 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:

1. Parenteral - >90% of HIV (+) individuals infected with HCV

2. Secretions

3. Sexual

4. 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

HEPATITIS D

Clinical outcomes: Co-infection

HDV + HBV

Healthy individual

Fulminant hepatitis

Recovery w/ immunity

Chronic HBV/HDV hepatitis

Cirrhosis Death

90% rare3-4%

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