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Hep B virion is a different family of viruses. It has a lot of really weird features about it. It also looks like a bunch of different viruses.
Explain its virion.
- 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
Genome of Hep B
- 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
Explain the special features of Hep B.
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
Hep B plus strand versus minus strand
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
Hep B coding regions in the genome are organized in a highly efficient fashion. Explain.
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.
Every base pair in the genome is involved in __. The genome also contains __ that __; a __; a __; and, __ that are involved in __.
coding for at least one viral protein
- two enhancer elements
- regulate levels of transcription
- direct repeats
- reverse transcription
Hep B has a __ with __
circular DNA genome
overlapping reading frames
Nucleocapsids enter the cytoplasm via __ and are _.
DNA Polymerase can __.
- transported to the nucleus
extend the plus strand, sealing the gap
Explain Hep B RNA
- 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)
Hep B genes and proteins
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
Virus history of hepadnaviruses in general
- 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
Explain the types of particles that Hep B has?
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
Explain the non-infectious viruses in most details.
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
How do immune systems divert the immune system?
may divert the immune system by binding to antibodies and complement, allowing less abundant virions to transverse the bloodstream undetected
There are __ major strains that exist and __ distinct serotypes.
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
Explain what is inside the Dane particle?
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
When the Hep B virus is made, it wants to replicate, but what?
It uses __ and __.
it doesn't get done when it's out
our own nucleases and ligases
Explain inside of our cells.
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
There are two __.
enhancer elements; this virus, because in our nucleus, uses the same language and machinery to get transcription of different RNAs
There are a few different starting sites.
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
The roles of the Hep B virus proteins: X
is not part of viral particle--nonstructural protein; does a lot of stuff
Roles of X
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
What happens if you add X by itself?
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
Hep B is what kind of virus?
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)
reverse transcriptase and ribonuclease H
when you have reverse transcriptase, you don't really need to replicate genome until you're in the virus particle
How is pre-genome RNA packaged?
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
Retrovirus vs Hep B
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
Retroviruses package an __ that is __ into DNA once it enters the host cell, whereas __ package a __ that is reverse transcribed from a __ in a cell during virus assembly.
- RNA genome
- reverse transcribed
- DNA genome
What else is distinct about the virus' method of exit?
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
Hep B incubation
- 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
Transmission of hep B
direct contact, body fluids, sexual contact, blood transfusions, contaminated needles, unprotected sex
Acute can be __. It can also be _.
Serum sickness: __
- mild to severe
- persistent (you can get it for a long time, getting associated disease)
your blood goes crazy trying to get things out
Prevention of Hep B
vaccines against it.
There are anti-hep B IG given from someone who had it to someone who had been exposed
WHy is Hep B persistent?
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
Recombivax is __
the first vaccine babies get because of maternal transmission
What are other treatments?
- 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
Drugs work--recombinant interferon
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
There are also drugs that work against __.
These drugs can sometimes be __.
- reverse transcriptase
- nucleoside analogs
Explain 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
How is Hep B transmitted?
by blood transfusions, contaminated needles, and unprotected sex
passage of virus from mom to newborn
A __ is available. __ can also be used to prevent infection via __.
- recombinant vaccine
- Anti-HBV immunoglobulins