Lecture 29
Hepatitis Viruses
Hepatitis: Inflammation of the liver
Causes:
Toxic (alcoholic), Infectious (parasites, fungi, bacterial, viral)
and Autoimmune.
Types:
Self-limited hepatitis: short duration, no carrier state
Chronic persistent hepatitis: virus persists without symptoms
Chronic active hepatitis: virus persists and causes necrosis, fibrosis
leading to cirrhosis and liver failure. May have
periods without symptoms. Symptoms include
jaundice, anorexia, flu-like, vomiting, nausea, colitis
and autoimmune disease.
Progression of Liver Disease
Fibrosis:
After becoming inflamed, the liver repairs itself and scarring occurs.
Cirrhosis:
Scars begin to join together, nodules may form, blood flow is
blocked. The liver shrinks and becomes hard.
Liver failure: Severe cirrhosis, liver is unable to filter wastes, toxins
and drugs from the blood. Does not produce clotting factors.
Healthy liver
Viral hepatitis
Liver
Largest internal organ
4 Functions
1. Purification…………removes drugs/toxins/ alcohol
2. Synthesis…………..protein metabolism, serum proteins,
bile, clotting factors
3. Storage……………..mineral, vitamins, sugars
4. Transformation…….converts hormones into active forms
Viral Hepatitis – Overview
Type of Hepatitis
Source and
transmission
Chronic
infection
Prevention
A
B
C
D
E
fecal-oral
Blood
sexual
Blood
sexual
Blood
sexual
fecal-oral
no
yes
yes
yes
no
immunization immunization blood donor immunization; ensure safe
screening;
drinking
water
risk behavior risk behavior risk behavior
modification modification modification
Hepatitis A Virus
HAV Overview

Small RNA virus

Non-enveloped

Picornavirus family Pico (greek very small) RNA virus
(Polio, Rhinovirus)

Single serotype

Acute or asymptomatic

Protective antibody confers lifelong immunity
 Acid stable
 Acquired from contaminated water, shellfish, salad
 22,700 cases in US per year, <0.4% cases are fatal
Symptoms of HAV

Children <6 years of age usually are asymptomatic (70%)

Usually (30%) anicteric (no jaundice)
 After an incubation period of 28 days……nonspecific illness
fever, malaise, anorexia,

Followed by gastrointestinal symptoms…nausea, abdominal discomfort,
dark urine and jaundice (70-80%)

Course of illness usually <2 months

15-20% of patients relapse lasting up to 6 months
 Acute liver failure is rare (0.015-0.5%)….usually young children and older adults
CONCENTRATION OF HEPATITIS A VIRUS
IN VARIOUS BODY FLUIDS
GEOGRAPHIC DISTRIBUTION OF HEPATITIS A
VIRUS INFECTION
Hepatitis A particles
consist of one RNA molecule surrounded by capsid proteins
Genomic RNA is infectious (1 million times less infectious than particles)
The HAV Genome
Capsid proteins
VPg
protease
polymerase
The structural and non-structural proteins and the highly structured
5´ and 3´ UTRs are represented.
HAV Life Cycle
HAV Life Cycle
The HAV life cycle. (a) The virus enters the hepatocyte via an interaction with a
cellular receptor. (b) This is followed by uncoating of the viral particle and release
of the positive-sense RNA genome into the cell. (c) An internal ribosome entry site
within the 5 nontranslated segment of the genome mediates cap-independent
translation of the viral polyprotein. (d) The polyprotein undergoes co- and posttranslational proteolytic processing directed by the viral protease, 3C. (e)
Nonstructural viral proteins assemble and commence synthesis of a negativestrand copy of the viral genome. (f) The negative-strand copy of the genome is
used as template for synthesis of multiple new copies of genomic positive-strand
RNA. (g) Some of this newly synthesized positive-sense RNA is recycled for further
RNA synthesis or translation. (h) Other positive-strand RNA molecules are
packaged into new viral particles formed by assembly of the structural proteins. (i)
Newly assembled HAV particles are secreted by the cell across the apical
membrane of the hepatocyte into the bile duct, from which they are passed into the
bile and small intestine.
HAV: Treatment and Vaccine
Treatment
Vaccine
99% of patients recover without treatment. Rest and
proper nutrition results in recovery at 2 months.
Cell culture-adapted virus grown in human
fibroblasts. Purified product inactivated with
formalin.
Hepatitis B Virus
HBV Overview

Enveloped virus

Double-stranded DNA virus

Family: Hepadnaviridae

350 million chronic carriers in the world (250 million in Asia Pacific)

In U.S. 1.2 million carriers, 5,500 deaths per year

Eight genotypes of HBV, designated genotypes a-h
Hepa*DNA*virus
Symptoms of HBV
 One third of world population has been infected with HBV
 One third of patients have “silent” disease
 Acute, recovery with immunity…………….90%
 Acute case fatality rate………………………1%
 Chronic liver disease……………………….10% → 25% cirrhosis + liver cancer
 Symptoms include: fever, headache, muscle aches, fatigue,
loss of appetite, nausea, vomiting and diarrhea, dark urine, abdominal pain,
jaundice.
Hepatitis B Virus Particles
Core
3.2 Kb DNA
polymerase
Surface
1. Replication
occurs in the
nucleus
2. Genomic
integration can
occur
3. Reverse
transcriptase
(RNA to DNA)
done in
particles in
cytoplasm
HBV Genome
HBV Genome
dsDNA
HBV Genome
dsDNA
RNA
HBV Genome
Surface Antigen
dsDNA
Polymerase
(RNA → DNA)
Core
RNA
Oncogene?
HBV surface antigen (HBsAg) is produced in vast excess
HBV: Treatment and Vaccine
Treatment
30-40% of patients recover with interferon.
Other antivirals such as nucleoside analogues are used.
Vaccine
Licensed in 1982. Purified surface antigen made
in yeast cells form natural-like particles.
Hepatitis Delta Virus
HDV Overview
 First isolated from liver biopsy from patients in Italy that had a more
severe form of HBV.
 Is a satellite virus of HBV.
 Uses HBV surface antigen for packaging and requires HBV (helper virus).
 HDV transmission similar to HBV (blood, sexual contact).
 Small RNA virus or viroid encoding one protein (delta antigen).
 Viroid: smallest known autonomously replicating molecules, single-stranded
-closed circular RNA.
Superinfection vs Coinfection
Super-infection: HBV then HDV
Co-infection: HBV + HDV
70%-80% chronic liver disease,
HBV alone = 30%
more severe acute disease than HBV alone
HDV Particles
HDV Genome
1679 nt RNA
Genomic RNA >50% cytoplasm
Antigenome
nucleus
Problem…………..what is the host RNA polymerase?
No known human RDRP(?)…………….some evidence for RNA pol II
Two forms of the delta antigen
Large delta antigen is made by RNA editing


Genomic
*C
RNA Editing
Antigenomic
mRNA


*U




Genomic
*A
*
AUG
Antigenomic
*
G
*
AGG
mRNA
Stop codon
Read through translation
Small delta Ag is made
Large Delta Ag is made
Two forms of the delta antigen
Delta antigen -Small (dAg-S): replication
Delta antigen -Large (dAg-L): inhibits replication, required for virus assembly
(packaging) created by RNA editing of the mRNA,
which creates read through translation (19 aa longer)
HDV: Treatment and Vaccine
Treatment
Vaccine
Interferon alpha, liver transplant.
HBV vaccine.
Hepatitis C Virus
HCV Overview
 RNA virus
 Family: Flaviviridae (other examples include: yellow fever, West Nile, Dengue)
 9.5 Kb RNA
 Formerly called non-A, non-B Hepatitis
 Incubation period
10-70 days
 2% of the world population is now infected
Most HCV infections become persistent…….
 Acute illness
<20%
 Chronic infection
70-85%
 Cirrhosis
10-20%
 Hepatocellular Carcinoma
 Lead reason for liver transplant
1- 4%
Factors Promoting HCV Infection or Severity

Increased alcohol intake

Age > 40 years at time of infection

HBV or HIV co-infection

Male gender
Hepatitis C Virus Infection
United States

New infections per year
26,000

Chronically infected Americans
3.2 million

Deaths from acute liver failure
rare

Deaths from chronic disease
10,000/year
Sources of Infection for
Persons with Hepatitis C
Injecting drug use 60%
Sexual 15%
Transfusion 10%
(before screening)
Occupational 4%
Other 1%
Unknown 10%
Source: Centers for Disease Control and Prevention
New Cases of Hepatitis C Virus
New Infections/100,000
140
120
100
80
60
40
20
Decline in transfusion recipients
1960
1970
1980
1990
2000
HCV Genome
Structural Proteins
Core
E1
E2
nucleocapsid
envelope
IFN
p7
Nonstructural Proteins
NS2
Ca++
NS3
NS4A
NS4B NS5A
?
NS5B
IFN polymerase
viral proteases and cofactor
Current problems with HCV:
Chimp only animal model
No vaccine
Only effective treatment is interferon or
interferon+ribavirin
Genotype-specific IFN Response
Genotype
Sustained
Response Rate
+ Ribavirin
1
10-12%
40%
2
50%
70%
3
53%
70%
HCV: Treatment and Vaccine
Treatment
Vaccine
Interferon or combination Interferon plus ribavirin.
None.
Hepatitis E Virus
HEV Overview
 Non-enveloped single-stranded RNA virus
 Transmitted by fecal contamination of drinking water
 Zoonotic disease, swine is possible animal reservoir
 In US reported among travelers returning from high HEV-endemic areas.
 Fatality rate 1-3% (pregnant women 15-25%)
HEV is in its own class of viruses
(Norwalk)
(Rubella)
(HAV, Polio)
HEV Genome
ORF1 replication proteins
ORF2 capsid protein
ORF3 phosphoprotein
HEV: Treatment and Vaccine
Treatment
Vaccine
None available. Rest and proper nutrition
results in recovery at 2 months.
None.
Summary
1. Five viruses called hepatitis viruses
2. HAV is similar to polio, has a known receptor, there is a vaccine and
it is contracted through contaminated water or food.
3. HBV
is a small DNA virus, chronic state, can make DNA from RNA,
there is a vaccine and it is contracted through blood or sex.
4. HCV
is similar to WNV, is an emerging virus, chronic state,
is contracted through blood and sex, and is interferon-resistant.
5. HDV
is a defective virus or viroid that requires HBV for surface Ag,
has only one encoded protein, uses RNA editing to gain a
second protein product.
6. HEV
is most similar to rubella, is zoonotic, is a public health concern and
contracted through contaminated water.