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27 Cards in this Set
- Front
- Back
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Hepatitis A virus transmission
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Fecal-oral
-close personal contact -contaminated food or water -blood exposure (rare) |
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Hep A structure
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Icosahedral golfball
+ strand RNA |
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Hep A serologic course
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High ALT spike
-1-2 months after exposure -then goes down Diagnosis of acute infection by appearance of HAV IgM in serum IgM disappears and other anti HAV antibodies appear and persist for life |
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Pathogenesis and Immune Response to Hepatitis A Virus
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Infections occur often in epidemics - national and community
Fecal-oral exposure, viremia occurs with HAV in blood Major site of replication is hepatocytes, which show distinct cytopathic effects -> virus directly cytotoxic Only one serotype Long-term immunity after first infection - 1/3 of US population with evidence of immunity No chronic (long term) infection Vaccine is available - Formaldehyde inactivated virus |
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Concentration of Hep B in various body fluids
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High
-blood -serum -wound exudates Moderate -semen -vaginal fluid -saliva Low/not detectable -urine -feces -sweat -tears -breastmilk |
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Hepatitis B Virions
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-3,200 base virion DNA partially duplex
-negative strand of DNA complete, positive strand incomplete -viral RNA attached to plus strand, acts as a primer site for polymerase -C core protein, P polymerase, S surface antigen, X protein -Polymerase protein (reverse transcriptase) within core -Envelope containing Hepatitis B surface Antigen (HBsAg) – S protein -X – thought to transactivate viral and cellular genes |
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HBV Lifecycle
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Viral DNA transported to nucleus where it is converted to CCC - Covalently Closed Circular DNA
-can stay in cell forever DNA genome transcribed by cellular RNA PolII (step 5) into pregenome (full copy, long version) and shorter mRNAs Short transcripts go to ER where ribosomes translate to make S protein (surface antigen) -S protein goes from ER to golgi to plasma membrane where it has the ability to independently bud off of cell (vaccine is surface antigen) Long transcript goes to cytoplasm and makes capsid (C) and reverse transcriptase polymerase (P) Capsid encapsulates pregenome and polymerase -polymerase converts pregenome RNA into viral DNA -goes to plasma membrane and buds off |
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Pathogenesis of Hepatitis B Virus Infections
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Primary site of replication in hepatocytes, although viral DNA and RNA found in many other tissues
The virus is not directly cytolytic for the infected cells; it is thought that immune-mediated mechanisms contribute to cellular damage Strong link between HBV infection and development of hepatocellular carcinoma (HCC), after long chronic infection with persistent low-level liver damage. |
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Immune Response to Hepatitis B Virus
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Viral clearance influenced by cytolytic and noncytolytic CD8+ T cell response, neutralizing antibodies, apoptosis. ~30% of infected people have no symptoms
Chronic (long term) infection common; T cell response is thought to be very weak in these individuals Cirrhosis and hepatocellular carcinoma (~20 years later) Death from liver disease in ~15-25% of chronically infected Vaccine is available -recombinant HBsAg produced in yeast |
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Types of Hepatitis B Virus Particles
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1. Dane Particle – Full virion
2. Spheres - ~20 nm, 10^4-10^6 fold higher than Dane. 3. Filaments All three have HBsAg Can reach very high concentrations - 300 mg/ml serum Spheres are most numerous – 10^13 spheres/ml serum |
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Nomenclature for Hepatitis B Virus Particles and Antigens
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HBV virion – HBV, Dane Particle
Hepatitis B surface antigen – HBsAg, antigen on surface of virion or sub-virion particles. Hepatitis B core antigen – HBcAg Hepatitis B e antigen – HBeAg, antigenic peptide from core protein. Marker for active replication. Antibodies specific for the above antigens. Immune response has recognized virus component as foreign and created antibodies against the protein. e.g. Anti-sAg, Anti-c, Anti-e |
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Acute Hep B infection with recovery: Serological course
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First marker is appearance of HBsAg
-goes away Then IgM anti-HBc -key diagnosis -goes away Then anti-HBs -goes away Total anti-HBc persists for life and is marker for past infection -in combination with lack of HBsAg shows recovery from acute infection |
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Chronic Hep B infection: serological course
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HBsAg and anti-HBc IgG persist
Best diagnosis is negative for IgM anti-HBc and positive for HBsAg in serum |
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HBsAg - negative
anti-cAg - negative anti-sAg - negative |
Never exposed, never vaccinated
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HBsAg - negative
anti-cAg - negative anti-sAg - positive |
Immune due to vaccination using recombinant sAg
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HBsAg - negative
anti-cAg - positive anti-sAg - positive |
Immune due to previous infection which has resolved
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HBsAg - positive
anti-cAg - positive anti-cAg IgM - positive anti-sAg - negative |
Acute HBV infection. Any anti-sAg antibodies that have been made are complexed with the large amount of the sAg and are thus undetectable
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HBsAg - positive
anti-cAg - positive anti-cAg IgM - negative anti-sAg - negative |
Chronic HBV infection. All anti-sAg antibodies that have been made are complexed with the large amount of the sAg and are thus undetectable
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HBV Treatment
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-Interferon alpha - for HBcAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.
-Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance. -Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg. |
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Hepatitis C Virus - HCV
Overview |
Positive strand ssRNA genome
Enveloped with two spike glycoproteins – E1 and E2 Produces a polyprotein that is cleaved by both cellular and viral proteases |
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HCV transmission
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Injected drug use – sharing needle
Direct blood or fluid exposure Sexual Activity Perinatal Transmission |
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Hepatitis C Virus Infections
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Outcome correlated with +/- strong T cell response
Persistent infection in presence of anti-HCV antibodies. Escape mutant map to hypervariable region of E2 spike glycoprotein Persistent infection associated with progression to cirrhosis and then to hepatocellular carcinoma (HCC) As with HBV, persistent low level damage to liver may be mechanism. HCV can directly cause cytopathic effects. Recruitment of immune cells to liver may damage cells |
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HCV treatment
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Interferon - may be considered for patients with chronic active hepatitis. The response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment.
Ribavirin - there is less experience with ribavirin than interferon. However, recent studies suggest that a combination of interferon and ribavirin is more effective than interferon alone. |
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Targets of Anti-HCV Therapies
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Surface glycoproteins E1 and E2
Viral protease NS3 NS5A RNA dependent RNA polymerase |
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Hepatitis D (delta) Virus
Overview |
Roughly spherical particle, contains 1700 base single strand circular RNA genome
Hepatitis Delta Antigen (HDAg) is the only viral protein encoded by genome. HDAg is RNA binding protein to form nucleocapsid. Defective RNA virus, growth is dependent on Hepatitis B virus “helper” to supply HBsAg. Infected liver cells have >300,000 copies of genomic RNA in cytoplasm |
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Infection with Hepatitis Delta Virus
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Replicates only in hepatocytes, requires HBV co-infection
Two types of co-infection with HBV – Outcome is usually more severe hepatitis than HBV alone Coinfection at same time as HBV – acute, severe liver damage, higher rate viral hepatitis Superinfection of chronic HBV infected – proceeds to chronic infection with both viruses. Much higher rate of cirrhosis than HBV alone. |
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Hepatitis E Virus
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Icosahedral, nonenveloped, ssRNA genome, 3 open reading frames
Fecal - oral transmission. Not antigenically related to Hep A Most outbreaks associated with fecal contaminated drinking water. Several large epidemics have occurred in the Indian subcontinent and the USSR, China, Africa and Mexico. |
