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9 Cards in this Set

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From what family of viruses is HCV? And what are its other basic characteristics?

Flavivirus, has envelope, +ve sense RNA, induces expression of many ISGs

How is HCV spread?

Through blood mainly, similar to its flavivirus friends like yellow fever and dengue, but not through insects. Mainly through IV. Used to mainly be due to unsterilized blood transfusions, but now mostly spread by injection drug users, especially in the west.

What are the main difficulties in treating HCV?

First used Treatment of pegylated IFN and Ribavirin has numerous side effects, including flu-like symptoms and psychiatric effects*. (50% of people experience serious side effects!)

What's worse, as little as 50% of people under this therapy are successfully treated, depending on the genotype of HCV they are infected with (50-55% with HCV 1, 70% with other genotypes)

Add this to the fact that many patients are feeling very healthy when diagnosed, you can see why it's problematic to make them feel very ill... For 48 weeks!

What has been done to solve these problems?

Recently new drugs, such as telaprevir, can be used alongside pegIFN and Ribavirin to increase success rate to +70-75%... But this drug has worse side effects and still requires 48 weeks of hell.

Sofosbuvir + simeprevir was thus introduced, which has a 100% success rate, and only needs to be used for 12 weeks. The difficulty with this though is that sofosbuvir is highly expensive, although slightly less so than liver transplants, and cannot currently be given to everyone.

What are the main difficulties in studying HCV?

Up till very recently(?) there have been no cell cultures in which we can (routinely) grow HCV, and the only animal model that works is chimps. Chimps are highly regulated and thus difficult to use (only very last resort studies possible), additionally, there are serious ethical issues around using them.

(May need to study find out more)

"No effective routine culture model"

Describe the molecular organisation of HCV

HCV has a 10,000 nt +ve sense RNA genome, surrounded by a nucleocapsid, which itself is encased within envelop proteins. HCV associates with lipid droplets to avoid the immune system, and bind host cells.
HCV either binds LDs, or is straight up engulfed by them. Don't think scientist have confirmed which of the two is true, but one of them is.

Describe the genetic organisation of HCV

C E1 E2 () NS2 NS3 NS4 NS5A NS5B



Overview the HCV lifecycle

HCV enters the bloodstream, and then is found in the liver 3 days later in chimp studies, (NB HCV is found in other tissues, but still mainly targets the liver being hepatotropic*)




HCV associates with lipid droplets, which makes it harder to detect by the immune system, it then binds onto a whole host of receptors on the host cell, such as LDLR, and SRB1 before entering the host cell through the tight junctions

(Quick note on entry, it is thought that initial binding event, say to LDLR, induces the release of the lipid droplets (LDLs 'n' HDLs), and then further bindings induce activates signalling events in the host cell.




It then enters via tight junction... weird ain't it.




Nex --> the HCV envelope fuses with the endosome which took it in to release the nucleocapsid, and then this nucleocapsid uncoats to release the +ve sense RNA genome, which then begins to be translated by host ribosomes at the ER.




At this site, the polyprotein is thus made and cleaved via NS3 serine protease and helicase, NS2, and host protein (perhaps in that efefing order).




Next --> An antigenome -ve sense RNA is created for a template, presumably by the only RNA-dependant RNA polymerase present, NS5B. From this template, numerous HCV genomes are made.




Lipid molecules are then associated with HCV core proteins, and E1 and E2 (pretty much all the structural Gs) and HCV nucleocapsid is added until a virus is made.*




Once this virus is made, it is packaged in the Golgi apparatus, which also (i think) adds a lipid molecule, right before shipping it out of the cell in an exosome.
This exosome can actually enter DCs too, and DCs can recognise the virus through TLR7.




One more think G. HCV, through its NS4B protein, forms abnormal membranous webs, which indicates that the cell is infected.

Describe the clinical features and pathogenesis of HCV infection

Unlike the stealth HBV, which elicits No ISG expression, HCV evokes the expression of many of roughly 300 ISGs. How? Well step into my office:

RIG-I and MDA5 both recognise the HCV RNA in the host cells because... Well dsRNA isn't exactly normal. Earlier on in the in the infection, RIG-1 is the dominant pathway used to activate the production of IFNs, but later on, the MDA5 pathway becomes dominant. (NB NS3-4 cleave these to dampen the IFN response, but do not completely block it #epicfail).




After this both type 1 and 3 IFNs ( aplha and beta, then gamma respectively) are released onto the neighbouring cells and bind onto receptors activating the JAK-STAT pathway.


All of these IFNs ultimately activate ISG expression. This is mediated by the ISGF3 complex, which consists of phosphorylated STAT 1 and 2, and IRF9.




PKR a potent antiviral also induces IFN response. After binding to dsRNA of HCV, it then associates with MAVS to activate ISGs.




TLR3 also activates ISGS via the TRIF pathway, once recognising dsRNA in the endosomes.




Now HCV tries its best to counter this




First as aforementioned NS3-4B basically cleaves RIG-I ane MDA5... But it doesn't stop there, they also cleaves MAVS (which we now know associates with ds-RNA bound PKR to activate ISG expression.




Additinoally, NS5A acts against PKR... And the core protein does it's own dirt too. But that requires a whole need card, and I gotta jet.