Lec 11 Hepatitis B virus/ Hepadnaviruses Flashcards
Hepatitis B virus/ Hepadnaviruses
Very important human infectious disease. 2 bn people.
Causes cirrhoses and cancer in liver. More powerful than smoking!!
There is an effective recombinant HBV surface antigen.
High prevalence in south Africa, Asia (large populations) which are also affected by liver cancer.
Transmission
Contact from blood or body fluids, not casual contact. 100 times more infectious than HIV, survives longer in the blood, outside the body.
Transmitted verically from mother to child
Horizontally transmitted with blood and body fluids.
People w/ HBV have 240x greater risk for getting liver cancer
Different genotypes of HBV
Error prone reverse transcriptase.
Genotypes B and C are found in Asia, D and E in Africa.
Have different defences against vaccines.
Vaccines
Originally Heat killed vaccine.
Vaccine escape mutant: Gly to Arg mutation at position 145, linked to vertical transmission
HBV vaccine also prevents liver disease. Children vaccinated had significantly reduced chance of developing liver cancer. The children who did get the disease were probably from vaccine failure OR from not getting all 3 shots
HBV Genome
Hepadnavirus
Genotypes A - F
Enveloped, relaxed - dsDNA virus
Free particles made in huge amounts, not infectious. Non infectious viral cells are full of receptors b/c they act as IMMUNE DECOYS!
42 nm, 3.2 Kb.
NCTP receptor
Replicates in cytoplasm, has cccDNA in the nucleus! Infects hepatocytes of humans and primates AND tree shrooms.
There are closely related hepadnaviruses found in other animals
4 ORFs
The X files of HBV
E antigen: Pre-core/cire region. May be immune decoy, can cross placenta barrier.
S antigen: envelope
Polymerase: RT
X gene: Unknown! X gene is 1 of earliest way to fight the host’s Smc5/6, which would otherwise prevent viral cccDNA transcription! Allows virus to continue replicating
NA = nucleoside analogue
lymphoid system shows quasi species, reservoir for HBV
HBV Life cycle
Binds to NCTP receptor (bile acid transporter)
Uncoats
Delivers its genome into the nucleus, cccDNA is made.
cccDNA cannot be targeted by antiviral therapies! Difficult to cure HBV once its established.
Virus is DNA virus but uses reverse transcriptase.
Exists in host as quasi species which are selected from host immune system and antiviral drugs! Live HIV
Clinical tests
Most important HBV test is HBV surface antigen test, overproduced by virus in extreme amounts, indicates chronic infection.
Quantitative HBsAg detects it in nucleus
If you are vaccinated, you make anti surface antigens
If you have HBV core and surface antibodies and the surface antigens is negative, you have had the virus but it failed to infect you!
E antigen follows treatment responses
Genotype tests determine whether people respond to the antiviral treatments
ALT checks for liver damage
HBV Treatments
- Interferon: killing for a cure: kills liver cells w/ HBV to stop cccDNA from replicating, cannot use on people w/ cirrhosis and pregnant. Injection once / per week, stop treatment after a year, stops virus but has bad side effects!
- Nucleoside Analogues: chain terminator for HBV replication. Very effective, hard for virus to develop resistance. Does not cure the infection, you must take it for a long time before the virus stops working.
Nucleoside analogues
Red = cirrhosis
Proportion of cirrhosis w/ increased years decreases when on Tenofovir treatment.
Woodchucks
Closely related HBV, good for studying liver cancer. 100% of woodchucks develop liver cancer b/c an oncogene is activated.
Occult HBV: After clearance, there is low level of cccDNA replication, even though the virus has died, within lymphoid cells.
When the woodchucks are infected within immune cells only.
Liver Transplant Recipients
Many years after the transplant, a different viral quasi species emerge from plasma, liver, immune cells! But the viral genetic diversity is lower.
HIV Co-infection
If you have 2 lymphotrophic viruses together, patients on HIV therapy, even though they have cleared HBV,
In theor serum, HBV is found in low levels and cccDNA in HBVc’s
HBV is not found in helper T cells if HIV is also present,
HIV normally attacks CD4+! 2 viruses don’t get along in some cells!
PBMCs can cross placental barriers so infant gets infection despite getting vaccination. In all cases, there were difference in the viruses found in the compartments
Mother-to-child transmission
If they have HBV, the babies get HBV antibody.
If moms have too high viral loos viral escape occurs.
Should treat moms in 3rd trimester. Controversial
Tenofovir has no adverse infant outcomes.
