Hepatitis B

• At its core, it is a DNA virus
• Regular icosahedral capsid underneath a lipid envelope

Has a lot of non-infectious particles that are spherical and filamentous and lack a nucleocapsid

• one of the smallest DNA viruses known to infect anything
• --> circular and partly double-stranded with a single-stranded region of variable length; there are gaps that are single-stranded

When it replicates, it doesn't usually finish replicating the genome

• Neither DNA strand forms a covalently closed circle
• - The full length minus DNA strand is joined at its 5' end to a tyrosine residue in the P protein, a virus-coded DNA polymerase with reverse transcriptase activity

the plus strand is shorter than the minus strand because its synthesis is interrupted before completion, giving rise to the single-stranded region

The ends of DNA hare held together as a circle by Hydrogen bonding between short, repeated sequences called DR, near the 5' ends of both strands

Four partly overlapping open reading frames, designated C (capsid), P (polymerase), S (surface protein), and X (for a regulatory protein) are translated to yield seven different viral proteins.

coding for at least one viral protein

• two enhancer elements
• regulate levels of transcription

polyadenylation signal

packaging signal

• direct repeats 
• reverse transcription

circular DNA genome

overlapping reading frames

• fusion
• transported to the nucleus

extend the plus strand, sealing the gap

• pre-genome RNA is made, along with several mRNAs
• depends on reverse transcriptase
• transcription by cellular RNA pol II is influenced by two enhancer elements (Enh I and II)

uses our own RNA polymerases to make virus particles

has 5 different promoters and four reading frames

• seven viral proteins and genes
• - it is kind of impressive for a small virus
• - these viruses are pretty unrelated
• - protein X does a lot of weird stuff

• infect a lot of different animal hosts
• they are highly specific and involved; live in the liver and liver cells. As a result of this, it is hard to grow them in culture

Hep B itself is difficult to study; one system is duck hep virus

non-infectious particles that contain lipids and HBV surface proteins and infectious particles (Dane particles)

contain everything you could think of in the virus--surface proteins, polymerase, genome, Hep B core proteins, all working together

If you have this in your body, your liver will be affected

contains HBV surface antigen and lipids surrounding a core nucleocapsid

Dane has its own name because those particles are actually the majority of what's in your serum. When infected, our cells make some Dane particles but they make more decoy non-infectious viruses

they are like pseudoviruses made mostly of lipids and hep B surface proteins and contains no core proteins, reverse transcriptase, or viral genome DNA

they induce an immune response; and, our immune system will focus on the pseudo-infectious virions, leaving the Dane particles in the blood

may divert the immune system by binding to antibodies and complement, allowing less abundant virions to transverse the bloodstream undetected

• 8 
• 4

8 major strains with different genome sequence variations (genotypes) cause a variation in the disease and severity and response to interferon

4 distinct antigenic serotypes contain two pairs of mutually exclusive epitopes

surface proteins, polymerase, genome, core protein, all working together

• circular genome with two enhancers
• different open reading frames
• every single nucleotide encodes for at least one protein; and, a number encode for more than one protein. it is the same as the dane particle 

the genome has positive and negative strands. All the genes are on one strand--the actual coding strand

it doesn't get done when it's out

our own nucleases and ligases

Inside of our cells--the nucleus--there is transcription of a number of different RNAs. There's pregenome RNA, which is a template for making new viral genome molecules

enhancer elements; this virus, because in our nucleus, uses the same language and machinery to get transcription of different RNAs

five different promoter elements-- preC, pregenome, preS1, S, and X

preC RNA: DR1 elements and DR2; the RNA for this is longer than the genome; it makes a turn and then some

is not part of viral particle--nonstructural protein; does a lot of stuff

implicated in development of hepatocellular carcinoma

upregulates: c-src kinase, Ras/raf/MAPkinase, SAPK, protein kinase C, and Jak/Stat pathway, NF-kB

sequesters tumor suppressor protein p53

inhibits apoptosis mediated by Fas, tumor necrosis factor, and other

to a genome of mice, they are at an increased risk of developing liver cancer

turns on a lot of kinases and growth factors, stress response pathways, tumor suppressor proteins, things to turn off apoptosis

a non-cytopathic virus; cells don't die and crank out a little bit of virus for a long time

• encoded by transcripts
• formation of envelope and non-infectious particles 
• small, middle, and large HB surface proteins 
• --> related proteins that share domains because they have the small structure in it

largest one has a site for myristate--hydrophobic chain of proteins, which help it fold properly

like the capsid--inner symmetrical surface of virus

appears to help with packaging RNA into virus; taking it out of the virus helps an infection become persistent

RNA-DNA dependent DNA polymerase (reverse transcriptase)

when you have reverse transcriptase, you don't really need to replicate genome until you're in the virus particle

by interaction with polymerase and core proteins--replication occurs on pregenome RNA via reverse trasncription. 

• Polymerase binds
• Complementary sequences replace a piece of RNA with another strand, degrading it on the way down and making mroe nucleotides
• From that, it actually uses the last couple of nucleotdies as a primer to make the secondary strand, running out of nucleotides before it gets around again. 
• It waits until it gets into the nucleus of another cell

Hep B is a DNA virus when it gets into the cell, goes into the nucleus, doesn't integrate but remains free in a circular form, makes a set of five mRNAs with cellular RNA polymerase II, one acts as pgRNA and gets turned into DNA when its on its way out. Essentially, its a DNA virus outside of the cell

Retro: outside of cells, they are RNA that are reverse trascribed into DNA on the way in so it can integrate into our genome

• RNA genome
• reverse transcribed
• hepadnaviruses
• DNA genome
• pgRNA

uses our own ER and golgi and exocytosis pathways to its advantage

genes are transcribed, LS, MS, and SS proteins go to the ER

after transcription, they go to the cytoplasm and travels out after going through ER and Golgi

• up to half a year
• in the initial stages of infection, half of the patients are asymptomatic, while the others suffer from flu-like symptoms, jaundice, serum sickness, elevated liver enzymes in the blood
• 1% can get fulminant hepatitis

direct contact, body fluids, sexual contact, blood transfusions, contaminated needles, unprotected sex

• mild to severe
• persistent (you can get it for a long time, getting associated disease)

your blood goes crazy trying to get things out

vaccines against it. 

There are anti-hep B IG given from someone who had it to someone who had been exposed

because of the X and E proteins

Liver slowly degrades as IS tries to clear the system. You get a wonky liver infection and fulminant hep as the liver starts to shut down

• 1973: Dane particle ID'd
• Afterwards, the search for the vaccine started. What scientists figured out was that there was abundant particles in the blood. They could clear out what isn't infectious and treat it with chemicals to inactivate it. Then, they injected it into people. However, with an HIV scare, they had to find another way.

1986: recombivax replaced the other vaccine; it was teh world's first recombinant vaccine and a subunit vaccine

They took the surface antigen gene out of the virus, put it into yeast, and then found taht yeast could successfully make the antigen. They purified it off and it became the basic purified subunit vaccine

the first vaccine babies get because of maternal transmission

• antiviral drug treatment has real success
• 90% of people with Hep B will get it cleared

10% of the people will go chronic

80% of those 10% get hep cancer

cloned out recombinant interferon that has been treated so it lasts longer in the bodies. It is a way of ramping up the immune system

interferon could really work

• reverse transcriptase
• nucleoside analogs

Resemble nucleotides but something is not quite right about them. Some have changes in the pyrimidine structures. SOme have changes down where the sugar should be and have trouble with chaining elongation

a nucleoside analog that gets incorporated into Hep B reverse transcriptase; has a Sulfur and can no longer be added to the molecule

they terminate chain elongation

by blood transfusions, contaminated needles, and unprotected sex

passage of virus from mom to newborn

• recombinant vaccine
• Anti-HBV immunoglobulins
• immunoprophylaxis