Iahi: 3.2 - Hepatitis Viruses

Front 1

What are the different types of viral Hepatitis?

Back 1

- Infectious - A
- Serum - B, D
- Parenterally transmitted - C
- Enterically transmitted - E
- Other

Front 2

What are the most common causes of chronic viral hepatitis in the U.S.?

Back 2

- Hepatitis C - 3.9 million
- Hepatitis B - 1.25 million

Front 3

What kind of virus is Hepatitis A (HAV)?

Back 3

RNA Picornavirus

Front 4

How many serotypes of Hepatitis A (HAV) are there?

Back 4

Only a single serotype worldwide

Front 5

What kind of symptoms/disease are associated with Hepatitis A Virus (HAV)? How is it transmitted?

Back 5

- Acute disease and asymptomatic infection; no chronic infection due to protective antibodies
- Fecal-oral transmission that is spread via contaminated food, water, raw shellfish, poor hygiene (hand-washing)
- Most commonly spread by good handlers, daycare workers, and children

Front 6

Hepatitis A Virus (HAV):
- Genome type
- Type
- Structure

Back 6

- + strand RNA virus
- Picornavirus
- Icosahedral

Front 7

What characterizes the capsid of Hepatitis A Virus (HAV)?

Back 7

Stable to acid, drying, and detergents

Front 8

How does Hepatitis A Virus (HAV) enter cells?

Back 8

Via receptor that is enriched in the liver

Front 9

What happens to the RNA in Hepatitis A Virus (HAV)?

Back 9

Translated into 1 polyprotein which is cleaved to form mature products (typical of all picornaviruses)

Front 10

How is Hepatitis A Virus (HAV) different from other picornaviruses?

Back 10

It is not cytolytic - it is steadily being released/shed from infected hepatocytes

Front 11

What kind of cultures can Hepatitis A Virus (HAV) be cultured on?

Back 11

No good tissue culture system for Hepatitis A Virus (HAV)

Front 12

How is Hepatitis A Virus (HAV) transmitted?

Back 12

- Oral acquisition
- Crosses through intestines and into blood
- Goes to liver
- Released from infected hepatocytes in bile and stool

Front 13

What can eliminate cells infected by Hepatitis A Virus (HAV)?

Back 13

Natural Killer and Cytotoxic T cells; Antibody response also assists in viral clearance

Front 14

The disease symptoms of Hepatitis A Virus (HAV) are probably caused by what?

Back 14

Immunopathology in liver

Front 15

What is the incubation period of Hepatitis A Virus (HAV)?

Back 15

- Average 30 days
- Range 15-50 days

Front 16

Jaundice caused by Hepatitis A Virus (HAV) is most common in what age groups?

Back 16

< 6 years - <10%
6-14 years - 40-50%
> 14 years - 70-80%
(increased incidence with age)

Front 17

What are some rare complications of Hepatitis A Virus (HAV)?

Back 17

- Fulminant hepatitis (severe and sudden)
- Cholestatic hepatitis (bile can't flow from liver to duodenum)
- Relapsing hepatitis
- No chronic sequelae

Front 18

What is the clinical course of a Hepatitis A Virus (HAV) infection?

Back 18

- Incubation for ~30 days
- Virus shed in feces after ~ 2 weeks
- Virus detectable in liver biopsy and feces after ~ 2.5 weeks
- Virus in blood after ~ 3 weeks
- HAV-specific IgM antibodies after ~ 4 weeks (decline around 6-7 weeks post-ingestion)
- Icteric symptoms (if present) and elevated serum liver enzymes ~ 4.5 weeks
- HAV-specific IgG antibodies after ~ 5 weeks (IgG antibodies remain high even after disease course is over)

Front 19

How do you prepare an inactivated Hepatitis A Virus (HAV) vaccine?

Back 19

- Cell culture adapted virus grown in human fibroblasts
- Purified product inactivated with formalin
- Adsorbed to aluminum hydroxide adjuvant

Front 20

Who is recommended to have the Hepatitis A Virus (HAV) vaccine? Efficacy?

Back 20

- Infants
- People working in or traveling to areas with high incidence of HAV
- People with chronic liver disease
- People working with HAV
- Decreased frequency of HAV infection by 90% in the last 17 years

Front 21

Hepatitis E Virus (HEV):
- Genome
- Structure
- Type

Back 21

- + sense ssRNA
- Icosahedral
- Enteric virus, calicivirus family

Front 22

How is Hepatitis E Virus (HEV) transmitted?

Back 22

- Mostly associated with fecally contaminated drinking water
- Minimal person-to-person transmission
- U.S. cases usually have history of travel to HEV-endemic areas

Front 23

If a person has acute symptoms of hepatitis and they just returned from travel overseas, what should you consider? What areas are associated with this?

Back 23

- May be Hepatitis E Virus (HEV) infection (endemic and waterborne = purple)
- Mexico, Asia, parts of Africa

Front 24

The heterogenous appearance of this virus (multiple shapes of particles including long filamentous and round) indicates what virus?

Back 24

Hepatitis B Virus (HBV)

Front 25

What parts of the world are associated with increased prevalence of Hepatitis B Virus (HBV)?

Back 25

- Northern Canada and Alaska
- Parts of S. America
- Africa
- Asia

Front 26

What are the outcomes of a Hepatitis B Virus (HBV) infection by age at infection?

Back 26

- Infants tend to have chronic infections more commonly than symptomatic infections
- Older children and adults tend to have more symptomatic infections

Front 27

What type of Hepatitis B Virus (HBV) infection are infants more likely to have? Why? Significance/

Back 27

- Chronic infections because their immune system is not capable of eliminating the virus
- Significant because they will encounter more people over their lifetime and therefore this needs to be controlled so they don't spread it

Front 28

Hepatitis B Virus (HBV):
- Genome
- Type
- Structure / receptor

Back 28

- Partly dsDNA (circular)
- Hepadnavirus (genotypes A-H)
- Enveloped (receptor is Sodium/Bile Acid Cotransporter NTCB)

Front 29

What kind of receptor does Hepatitis B Virus (HBV) bind to?

Back 29

Sodium/Bile acid Cotransporter (NTCB) found in GI system

Front 30

What happens after the genome of Hepatitis B Virus (HBV) is released into the host cell?

Back 30

- Starts as circular DNA genome, partly double-stranded
- Genome enters, DNA synthesis occurs to form fully ds DNA
- Genome goes to nucleus, transcribed to mRNA
- mRNA translated in cytoplasm
- mRNA reverse transcribed to ssDNA, DNA made partially ds
- DNA encapsidated into new virion on ER and enveloped and released

Front 31

Which types of Hepatitis do not have a good tissue culture system?

Back 31

- Hepatitis A
- Hepatitis B

Front 32

Why is it hard for Hepatitis Viruses to be cultured on tissue?

Back 32

Liver is highly active but not proliferating - in a culture you want cells to grow but the more they grow the less liver like they are (harder for hepatitis viruses to grow)

Front 33

Hepatitis B Virus (HBV) infected cells produce what?

Back 33

- Infectious virus
- Non-infectious "HbsAg" particles (antigens without DNA - immunogenic but not infectious)

Front 34

What is the foundation and concept for vaccines?

Back 34

Antigen without DNA - immunogenic but not infectious (e.g., Hepatitis B Virus (HBV) makes non-infectious "HbsAg" particles)

Front 35

What are some reported risk factors for acute Hepatitis B Virus (HBV) in U.S.?

Back 35

- Unprotected sex (heterosexual and MSM)
- IDU (intravenous drug use)
- Blood products
- Birth

Front 36

What is the path of Hepatitis B Virus (HBV) infection and spread throughout the body? How does the immune system try to counter HBV?

Back 36

- Initial infection: blood, sex, IV drug use, neonatal, etc.
- HBV enters blood
- Antibodies can prevent spread and disease
- If not, HBV spreads to liver
- Liver releases HBsAg that can cause immune complexes and disease
- Liver also can cause viremia if the cell mediated immunity cannot handle it
- If progresses to viremia, spreads in mother's milk, vaginal secretions, blood, semen, saliva
- These body fluids can transmit to new hosts

Front 37

What symptoms occur during the incubation period of Hepatitis B Virus (HBV)?

Back 37

~15% have fever, rash, and arthritis

Front 38

What symptoms occur during the acute disease phase of Hepatitis B Virus (HBV)?

Back 38

- Jaundice
- Dark urine
- Malaise (95%)
- Anorexia (90%)
- Nausea (80%)
- RUQ pain (60%)
- Itching (10%)

Front 39

Antibodies to what parts of Hepatitis B Virus (HBV) are made and in what order?

Back 39

- First - Anti-HBc (core structures)
- Next - Anti-HBe
- Later - Anti-HBs (surface antigens)

Front 40

What are the clinical outcomes of Hepatitis B Virus (HBV) infections in adults?

Back 40

- 90% reach resolution
- 1% get fulminant hepatitis (severe and sudden)
- 9% are HBsAg+ for > 6 months

Front 41

What are the possible outcomes of an acute Hepatitis B infection when the patient is HBsAg+ for > 6 months?

Back 41

- 50% reach resolution
- Some are asymptomatic carriers
- Some get chronic persistent hepatitis (may cause extrahepatic disease, polyarteritis nodosum, glomerulonephritis)
- Some get chronic active hepatitis (may lead to cirrhosis, hepatic cell carcinoma or the extrahepatic disease)

Front 42

What are the possible outcomes of an acute Hepatitis B infection when the patient is HBsAg+ for > 6 months that leads to Chronic Persistent Hepatitis?

Back 42

Extrahepatic disease:
- Polyarteritis nodosum
- Glomerulonephritis

Front 43

What are the possible outcomes of an acute Hepatitis B infection when the patient is HBsAg+ for > 6 months that leads to Chronic Active Hepatitis?

Back 43

- Extrahepatic disease: Polyarteritis nodosum and Glomerulonephritis
- Cirrhosis
- Hepatic Cell Carcinoma

Front 44

What outcomes from an acute hepatitis B infection can lead to Hepatic Cell Carcinoma?

Back 44

- HBsAg+ for > 6 months (9%)
--> Chronic Active Hepatitis
--> Hepatic Cell Carcinoma

Front 45

What con influence the outcome of a Hepatitis B Virus (HBV)?

Back 45

- Immune control
- Presence of HDV (Heptatis Delta Virus agent)

Front 46

If there is an effective cell-mediated immune response to Hepatitis B Virus (HBV), what happens?

Back 46

- Acute disease (jaundice, release of enzymes)
- Resolution

Front 47

If there is a limited cell-mediated immune response to Hepatitis B Virus (HBV), what happens?

Back 47

- Chronic disease w/ mild symptoms
- Can lead to: fulminant hepatitis, primary hepatocellular carcinoma, or cirrhosis

Front 48

What does the presence of Delta agent affect Hepatitis B Virus (HBV) chronic infections?

Back 48

Leads to Fulminant Hepatitis (severe and sudden onset)

Front 49

What is Hepatitis Delta? What are its limitations?

Back 49

"Viroid" - can only grow in Hepatitis B infected cells

Front 50

What is the genome of Hepatitis Delta? How is it copied? What does it encode?

Back 50

- Small RNA, copied by host RNA polymerase II, catalytically active "ribozyme" that processes itself
- Encodes 1 antigen (protein), becomes packaged in Hepatitis B sAg

Front 51

What is the difference between a Hepatitis D coinfection and a superinfection?

Back 51

- Coinfection - Hepatitis B and Hepatitis D at the same time
- Superinfection - Hepatitis D subsequent to Hepatitis B infection

Front 52

What are the characteristics of a Hepatitis D / B coinfection?

Back 52

- Infected at the same time
- Severe acute disease
- Low risk of chronic infection

Front 53

What are the characteristics of a Hepatitis D / B superinfection?

Back 53

- Hepatitis D subsequent to HBV infection
- Usually develop chronic HDV infection
- High risk of severe chronic liver disease

Front 54

Why does chronic Hepatitis B Virus (HBV) infection correlate with a high incidence of Hepatocellular Carcinoma (HCC)?

Back 54

- Injury to liver causes sustained cell proliferation of cells that are usually quiescent, enabling genetic errors to accumulate
- Integration of viral DNA into host chromosome (in >85%) causes genomic instability and can lead to alterations in host gene expression
- Virally encoded "X" protein linked to signal transduction cascades that can be oncogenic (X decreases p53 activity as well as affecting other key pathways)
- In "transgenic" mouse models of HBV oncogenesis, HCC is correlated with surface antigen expression (causes liver injury, hyperplasia, inflammation) and X expression

Front 55

What factors have lead to a decrease in incidence of acute Hepatitis B in the U.S.?

Back 55

- Vaccine
- HBsAg screening of pregnant women
- Infant immunization recommendation
- Adolescent immunization recommendation

Front 56

How do you prevent Hepatitis B Virus (HBV)?

Back 56

- Screen blood supply
- Vaccination to prevent infection of high-risk individuals and infants
- Universal blood/body fluid precautions
- Lifestyle precautions

Front 57

How is the Hepatitis B Virus vaccine made?

Back 57

Subunit vaccine - recombinant HBsAg produced in yeast, which self-assembles into immunogenic particles

Front 58

How do you treat Hepatitis B Virus (HBV)?

Back 58

- Polymerase inhibitors, nucleoside analogs, IFN-α (7 licensed drugs; resistent viruses do appear)
- New approaches to "silencing" HBV expression during chronic infection

Front 59

What is the most prevalent NANB Hepatitis Virus?

Back 59

Hepatitis C Virus (HCV)
(NANB = Non-A, Non-B)

Front 60

Hepatitis C Virus (HCV):
- Genome
- Structure
- Type

Back 60

- + strand RNA virus
- Enveloped virion (associated with cellular LDL and VLDL)
- Flavivirus

Front 61

What causes the variety of quasi-species of Hepatitis C Virus (HCV)?

Back 61

Error-prone RNA polymerase

Front 62

What does Hepatitis C Virus (HCV) encode? Function?

Back 62

Multiple immunomodulators - enables virus persistence

Front 63

What causes the symptoms of Hepatitis C Virus (HCV)?

Back 63

Liver damage primarily due to immunopathology - viral replication induces robust innate immune response

Front 64

What factors lead to the spread of Hepatitis C Virus (HCV) through the population?

Back 64

High incidence of chronic and asymptomatic infection

Front 65

What is Hepatitis C Virus (HCV) associated with the development of?

Back 65

Hepatocellular Carcinoma (delayed onset)

Front 66

When was Hepatitis C Virus (HCV) identified? Therapies developed?

Back 66

- Identified in 1989
- Interferon-α and ribavirin combination therapy developed in 1998
- Very fast development

Front 67

What are the steps of the Hepatitis C Virus (HCV) life cycle?

Back 67

1. Entry into host cell
2. Uncoating
3. IRES-mediated translation; proteolytic processing
4. Membrane associated RNA replication in membranous web (anchors RNA and machinery together)
5. Assembly into virions
6. Maturation and release

Front 68

How many Hepatitis C Virus (HCV) virions are released per day?

Back 68

10^12 virions/day

Front 69

What are sources of infection for Hepatitis C?

Back 69

- Injecting drug use (60%)
- Sexual (15%)
- Transfusion (before screening) (10%)
- Occupational (4%)
- Other (nosocomial; iatrogenic; perinatal) (1%)
- Unknown (10%)

Front 70

What is the serologic pattern of Hepatitis C Virus (HCV) acutely and chronically?

Back 70

- Strong Antibody (anti-HCV) response after a couple of months
- Large increase in liver enzymes (ALT) above normal suggests liver damage - very high acutely

Front 71

What was the main factor in decreasing the incidence of Hepatitis C Virus (HCV) infections in the U.S.?

Back 71

1992 - widespread screening of blood supplies
(remaining due to IV drugs, sex, etc.)

Front 72

What are the clinical outcomes of a Hepatitis C Virus (HCV) infection in adults?

Back 72

- 15% - recovery and clearance
- 85% - persistent infection that leads to chronic hepatitis
--> in 6% leads to liver failure, in 20% leads to cirrhosis, in 4% leads to hepatocellular carcinoma

Front 73

What proteins from chronic Hepatitis C Virus (HCV) infection lead to an increased incidence of hepatocellular carcinoma?

Back 73

- HCV Core protein
- HCV Envelope protein (E2)
- Non-structural protein NS3
- Non-structural protein NS5A

Front 74

What are the actions of HCV Core protein that can increase the incidence of Hepatocellular Carcinoma?

Back 74

- HCV core protein interacts with, and regulates, many cellular tumor suppressors (such as p53, Rb) and signal transduction pathways involved in proliferation
- HCV core protein induces steatosis (lipid accumulation), leading to “fatty acid spiral”, oxidative stress and increased cell proliferation
- Steatosis accelerates development of HCC

Front 75

What are the actions of HCV Envelope protein (E2) that can increase the incidence of Hepatocellular Carcinoma?

Back 75

HCV envelope protein (E2) inhibits natural killer cells and can activate cell proliferation pathways

Front 76

What are the actions of HCV non-structural protein NS3 that can increase the incidence of Hepatocellular Carcinoma?

Back 76

NS3 can enhance cell growth and block the action of the p53 tumor suppressor

Front 77

What are the actions of HCV non-structural protein NS5A that can increase the incidence of Hepatocellular Carcinoma?

Back 77

NS5A can enhance cell growth, prevent the action of p53 and prevents apoptosis

Front 78

What happens to transgenic mice expressing HCV core protein?

Back 78

Develop Hepatocellular Carcinoma (HCC)

Front 79

What does Hepatitis C Virus (HCV) infection require?

Back 79

Cellular miRNA (micro RNA) - miRNA-122 (most abundant mRNA in liver) binds to 2 sites in the 5'UTR (untranslated region) of the HCV genome, ENHANCING translation and/or replication

Front 80

What are micro RNAs (miRNA)?

Back 80

Small, processed RNAs that regulate other mRNAs in a sequence-specific manner

Front 81

What happens if there is a deletion of miRNA-122? How can this happen?

Back 81

Impairs infection of Hepatitis C Virus (HCV) in tissue culture and in infected chimpanzees (SPC3649 targets miRNA-122 and leads to its depletion)

Front 82

What kind of studies were done on Hepatitis C Virus (HCV) to determine which patients clear HCV infections vs. those that develop chronic infections and which patients respond to treatment with pegylated IFN and those who do not?

Back 82

Genome-wide association studies (GWAS) to identify genetic polymorphisms

Front 83

Genome-wide association studies (GWAS) done on Hepatitis C Virus (HCV), showed what results?

Back 83

- IL28B gene plays a key role in the outcome of HCV infection
- IL28B encodes the antiviral cytokine IFN-λ (lambda)
- A polymorphism within IL28B has a strong impact on the development of chronic infection and on the responsiveness of IFN therapy

Front 84

What Hepatitis C Virus (HCV) genotype is the most prevalent in the U.S.? Implications for treatment?

Back 84

- Genotype 1 (73%)
- Only 42-46% of patients with Genotype 1 had no HCV RNA 24 days after treatment (Sustained Virological Response w/ IFN/Ribavrin) cessation as opposed to 76-82% of non-Genotype 1 patients

Front 85

Which drugs are used for treatment of Hepatitis C Virus (HCV)?

Back 85

IFN + Ribavirin (also other new HCV protease inhibitors) --> work better on non-1 genotype HCV

Front 86

Which kinds of Hepatitis are responsible for causing acute hepatitis (generally not severe)?

Back 86

Hepatitis A, B, and E

Front 87

How are Hepatitis A and E transmitted?

Back 87

- Fecal-oral route
- Virus shed before symptoms, increasing rapid spread throughout local population

Front 88

What is the most important step in stopping transmission of Hepatitis A and E?

Back 88

Hygiene!
(also an inactivated vaccine for Hepatitis A)

Front 89

Which kinds of Hepatitis are responsible for causing chronic hepatitis?

Back 89

Hepatitis B and C

Front 90

How are Hepatitis B and C primarily transmitted

Back 90

- Blood products (not in official blood supply anymore)
- Shared needles (drug users, tattoos)
- Sexual transmission

Front 91

What kind of vaccine is used for Hepatitis B? Who should receive it?

Back 91

Recombinant sAg - safe and effective (goal is vaccination of all infants in US)

Front 92

If we can prevent Hepatitis B and C infection, what can we prevent?

Back 92

- Chronic disease, spread, and hepatocellular carcinoma
- Also, elimination of Hepatitis B will eliminate Hepatitis D infection