HCV itself may be cytopathic

[mikesimon]

Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes.
Walters KA, Syder AJ, Lederer SL, Diamond DL, Paeper B, Rice CM, Katze MG.

Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America.

The mechanisms of liver injury associated with chronic HCV infection, as well as the individual roles of both viral and host factors, are not clearly defined. However, it is becoming increasingly clear that direct cytopathic effects, in addition to immune-mediated processes, play an important role in liver injury. Gene expression profiling during multiple time-points of acute HCV infection of cultured Huh-7.5 cells was performed to gain insight into the cellular mechanism of HCV-associated cytopathic effect. Maximal induction of cell-death-related genes and appearance of activated caspase-3 in HCV-infected cells coincided with peak viral replication, suggesting a link between viral load and apoptosis. Gene ontology analysis revealed that many of the cell-death genes function to induce apoptosis in response to cell cycle arrest. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Regulation of numerous genes involved in anti-oxidative stress response and TGF-beta1 signaling suggest these as possible causes of delayed cell cycle progression. Significantly, a subset of cell-death genes regulated during in vitro HCV infection was similarly regulated specifically in liver tissue from a cohort of HCV-infected liver transplant patients with rapidly progressive fibrosis. Collectively, these data suggest that HCV mediates direct cytopathic effects through deregulation of the cell cycle and that this process may contribute to liver disease progression. This in vitro system could be utilized to further define the cellular mechanism of this perturbation.

http://tinyurl.com/dfvgd4

Mike

[eureka254]

Perhaps in the not too distant future your analogy will be true:

Our future world will be a world where everyone with hep c is svr and wonderbread won't get hard even if you leave it out... :)

[eureka254]

"It is my understanding that it is pretty well settled that our immune response to the virus causes liver damage. It was believed by many that HCV, in and of itself, was not cytopathic - it did not cause damage."
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I'm certainly no microbiologist, but I've definitely harbored the (unpopular) opinion that current 'understanding' -- attributing hcv damage to immune response -- was fairly lacking.  The very varying responses of individuals to VL, disease progression, clearance vs chronic, etc. yet still attributing liver damage solely as a 'immune response'  mechanism has been a vaguely unsatisfactory explanation for me.

Coming from the perspective of exploring the nature of HCC in hcv and finding it not always linear with cirrhosis progression always led me to be suspicious of the presumption that the hep virus wasn't in some way cytopathic -- especially on a gene expression/suppression or cellular regulation/replication level.  (The nature of viral replication to NOT be cytopathic was always counter-intuitive to me, anyway.)

Definitely noteworthy, thanks!
~eureka

[FlGuy]

Bill Nye has nothing on you. Now, if you could just put it to rhyme like Sesame Street...

[mikesimon]

It is my understanding that it is pretty well settled that our immune response to the virus causes liver damage. It was believed by many that HCV, in and of itself, was not cytopathic - it did not cause damage. This "immune response is the cause of damage theory" appeared to explain why some people with a low viral load sustained significant liver damage while some people with a high viral load experienced little liver damage. This article suggests that the virus is indeed cytopathic and makes the observation that:

"Maximal induction of cell-death-related genes and appearance of activated caspase-3 in HCV-infected cells coincided with peak viral replication, suggesting a link between viral load and apoptosis".

I found that newsworthy.

Mike

[jmjm530]

The analogy falls apart a little because damage done by the air (immune response) , i.e. the bread hardening, cannot be reversed simply by killing the ants, but thankfully the liver was baked a little bit more intelligently than wonderbread and it apparently will soften (fibrosis regression) after successful extermination (SVR).

[jmjm530]

FL: Every once in a while I can sometimes understand the gist of an article like this.  I did not understand one sentence of this one.
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Look at it this way. The liver is a slice of fresh Wonderbread. If it's left out of the fridge too long it starts to harden (fibrosis) because of exposure to the air (immune response). Now they think the reason the bread is hardening is because some ants (the virus) snuck in through the window and their saliva is somehow reacting with the dough. So, if you call the exterminator (your doc) and exterminate (SOC) then you kill the ants and the bread becomes nice and soft again because the ant saliva is no longer reacting with the dough.  On the other hand, if you can't kill the ants (relapse/non-response), then maybe you can find out what's in the saliva that makes the bread harden and come up with an antidote (an anti-fibrotic). Not sure if you remember the "moth" problems I had during treatment? I now wonder if there's some sort of connection :)

[jmjm530]

PA,

Meant "regression"! Thanks for the correction.

Apache,

I think you got the gist of it but just keep in mind the first sentence which reinterates that these mechanisms of liver injury are not fully understood, so I'm not sure they're necessarily saying that even the immune-mediated processes cause fibrosis -- but that they *think* those immune-mediated  processes might and that they now *think* that the virus itself might as well through deregulation of the cell cycle.

-- Jim

[apache1]

What i get from this paper is,  now researchers are finding that not only does the immune system response to hcv cause cell damage, but also now they are finding that the virus infected cells also cause cytopathic effects (degenerative changes in a cell from multiplication of virons in that cell)

Not sure if this is a correct interpretation or not...maybe someone with more knowledge of microbiology with help us understand.

[portann]

It's articles like this in which I could have understood the exact opposite of what's said.

This is what I took from it:

1) Study done with acute HCV

2) Link suggested between viral load and apoptosis

3) Study suggests that HCV creates pathological change in cells which may lead to progression in liver disease.

Jim, did you mean  "to help augment SVR induced fibrotic progression" or "SVR induced fibrotic regression"?

[FlGuy]

Every once in a while I can sometimes understand the gist of an article like this.  I did not understand one sentence of this one.

[jmjm530]

We  already know from study data that SVR confers among other things the probability of fibrosis regression. This study appears to explain at least one mechanism  (in a reverse sort of way) by stating that fibrotic progression is in part the direct result of the virus through deregulation of  the cell cycle. Hopefully, once these mechanisms are better understood, new and better anti-fibrotic agents can be developed to help augment SVR induced fibrotic progression where necessary or replace it where SVR cannot be attained. Thanks. for posting.

-- Jim