Therapeutic Vaccine Targets HCV

This surely sounds like a promising new development for HCV. We can't deny the fact it is our own immune systems that need the right terrain to beat down the virus. Hopefully, the Intercell vaccine will be the ticket for those who currently have resistance to SOC tx.
It breaks my heart to read of those that fight so hard and endure treatment, then end up dealing with a relapse. Keep the faith. Something's bound to happen with all of the latest developments in the works.

Anyone have any thoughts or input on the vaccines? www.intercell.com is the one I have bets on... : )

http://www.bionity.com/news/e/67725/

[Ginger12521]

Smart Vaccines
Most of the content of a conventional vaccine is not needed to induce immune response. Intercell's smart vaccines consist only of the absolutely necessary components.

Behind Smart Vaccines
Many existing vaccines consist largely of inactivated organisms, like viruses and bacteria. Such vaccines contain, along with the protective antigens, numerous components that are unnecessary and cause side effects. We specialize in minimizing the set of components needed. In fact there are only two: the antigen(s), which gives the vaccine its specificity against a certain organism, and the Immunizer (adjuvant), which activates the immune system in a way that enables it to recognize the antigen and trigger a strong immune response. One of our programs deals with identifying novel adjuvants, and another with novel antigens. These are Intercell's core technologies. They result in innovative vaccines that contain only the essential components needed to activate the immune system.
Such a vaccine is easier to produce, and is safer because it does not contain living organisms, focuses better on the immune system, and is likely to have fewer side effects. That is what we call a "smart" vaccine.

Smart Vaccines Work
The starting point for the development of smart vaccines is the human immune system, and the way it tackles a given disease. The molecules detected with the help of the human immune system are the most effective. Our core technologies provide an outstanding source of our own products and give rise to lucrative partnerships. This is what makes our company competitive.
The information for identifying antigens is imprinted in antibodies from individuals who have had an encounter with a specific pathogen and have destroyed it through their inherent antibody response. By carefully analyzing a patient's response, it is possible to learn which antigens his/her immune system recognized and how it threw off the disease. These findings open the way for eradicating a pathogen and developing a vaccine.

[dointime]

I know that this topic comes up time and again but please bear with me as I still don't understand.  We know that viral load does not equate to liver damage - counterintuitive but an established fact I believe.  We also know that liver damage is caused by the inflammation which occurs when the immune system fights the virus.  So if this vaccine is intended to ramp up the immune system but not eliminate the virus then isn't the result just going to be more inflammation -> more liver damage?

Now, I don't think that a lot of clever people would be developing the vaccine if my logic on this were actually correct, and it would be great to think that HCV could be controlled in a beneficial way with a vaccine.  So could somebody please explain where I'm going wrong in my figuring on this so that I can finally get it.

Thanks
dointime      

[Hepatitis Researcher]

Therapeutic vaccines for mainly HBV and HCV are indeed my special interest and i worked actively in several of these developments ( basic  and clinically)  and as a consultant/ advisor to the respective industry.

So I feel competent to answer these questions.

dointime: "We also know that liver damage is caused by the inflammation which occurs when the immune system fights the virus.  So if this vaccine is intended to ramp up the immune system but not eliminate the virus then isn't the result just going to be more inflammation -> more liver damage? "

This is a good question. To understand the answer some refinements in the understanding of the way the immune system reacts to the virus and how it targets the virus  and how it damages or protects the liver are needed.

The HCV virus/its "antigens'    activate the immune system in 3 fundamentally different ways: 1, 2a and 2b ddescribed below:

1. More primitive/ancient ways to react in nonspecific fashion to an intruder are activated: Unspecific figther cell - macrophages, "Kupfer cells", "Natural Killer cells (NK) - are secreting proinflammatory cytokines - like TNFalpha and Il-beta, Il-6 and ahost of other signaling molecules that participate in a self enhancing "cross talk' between immune cells and also directly activate the production of Hydrogen Peroxide, NO, Nuclear Factor Kappa B in themself and the cells surrounding them.

This often leads to the  partial destruction of invading microorganisms, but also produces a lot of damaging effects to the tissues in which this fighting occurs, in this case mainly the liver. This is also part of the old "innate immune response", that was in existence long before the more refined and effective ways to fight invading microorganisms was developed in our evolution. In summary: A lot of fighting with low efficacy and a lot of collateral damage.

2. Later, to defend us better with less self damage inflicted by "defending" , we invented the so called "adaptive immune response". Here highly specific aspects of the actual invading organism are used and recognized to concentrate and focus the defense with less collateral damage.

2a. By producing antibodies specific to the structure  of the outer shell of the invader we are able to inhibit, by simple binding and coating - without a lot of self damaging extra "activation" its entry inside our cells, threby no further spread of the infection occurs and everything fades to nothing without much illness at all. Thats how the HBV vaccine works ( the prophylactic one).

2b. In all body surfaces we have high numbers of highly specialized "sentinel" cells,  "dendritic cells" sitting and lurking for invaders.
When they locally encounter an HCV invader on its slow way in , eg at the mucosal entry site in the superficial tissue after sex, or in the skin after kittys infected claws have scatched, they engulf the invading virus - like in the old days, because their grandfathers were macrophages, predator cells, that know how to atttack and "eat and digest" and process its proteins/antigens  in a highly specific fashion, cutting them into short specific peptides either 10 or 20 amino acids long - these pieces are called epitopes.

The dendritic cells then actively move these pieces to their surface, bound to specific proteins called MHC class I and class II, that have well suited grooves on them, to which those viral protein pieces fit.

The whole thing ( MHCs with bound epitopes on them)  now  protrudes  to the outside of the dendritic cells. While doing the eating and processing, the dendritic cells have actively moved from their lurking position in the tissues (eg skin or vagina or oral cavity) to the local lymphnodes, where the real adaptive immune function drama will now start.
Up to now we are still in the "innate branch of the adaptive immune system. But now the superior technology of late evolution finally comes into play.

The human body has produced, by somatic mutation and complex recombination, a huge array of tens of thousands ENTIRELY DIFFERENT  types of T and B lymphocytes. Just a few dozen  of  the individual kind  are initially present. They are called naive lymphocytes  and most of them never do anything but wait for their time to function that never ever comes.

But now something happens that is close to a miracle: All these naive lymphocytes are constantly checking the incoming (into the lymphnodes where the action happens) dendritic cells, these are showing their cut up prey- the engulfed HCV virions -  like a butcher would show his pieces of meat prepared from an animal that he has carefully dismantled.
They are in a long long but very efficient line, to test one by one if these epitopes presented fit their individual surface recognition molecules - The Tcell receptor. The vast majority does not fit and simply moves one.

But if and when, in the rare rare instances where  there is a precise fit between the offered epitope and the T-cell receptor , - an extremely sensitive and specific interaction-  a truly dramatic chain of events is initiated.  
The one precisely fitting T cell is now positively selected to be the specific fighting machine against the very intruder ( HCV) on hand and will receive "a licence to kill", ( class I, or Cytotoxic T lymphocyte or Killer cell")  or a licence to make a ton of activation noise and signaling (class II "helper"Tcell) and most importantly a license to reproduce rapidly -  "proliferate" - so as to rapidly produce huge numbers out of a single naive lymphocyte. That could mean dozens  of billions of specific progeny for that very cell. How exiting for that lucky lymphocyte!

And more than that, it also gets endowed - all by the dendritic cells that is the "authority" that gives out these licenses- with extra weapons, like the capacity to exude antivirals like gamma and alpha interferon, surface power drill like weaponry enabling it to drill deadly holes in infected cells, furthermore the authority to issue suicide orders to the infected cells they encounter and furthermore the license to spray the whole neighborhood of infected cells with antivirals. Broad powers in a state of war indeed, but only to those highly trained and specifically qualified.

[Hepatitis Researcher]

Continued from above:

This immune response is "adaptive" becuse a huge number of defense cells is produced that are specifically adapted to only - with extreme precision!! - recognize pieces of that one invader - HCV - and nothing else! That specificity makes this type of defense so much more effective and less hurtful for the infected organism.

How do these "CTLs" lymphocytes, now swarming out and searching the whole body for HCV infected cells, recognice a cell that is infected?  Simple: Like an army of green barrets equipped with ultra high tech testing devices, they check the trash can of every house in the country ( cell) , to see if some tiny piece of trash from the harboring of these pesty Martians in the house can be found in the can.
They have no warrant to search the house, but their detection device for Martian body parts is so incredible sensitive and specific, that a single molecule on a hepatocyte can be enough to sound the alarm. Then the license to kill and also to spray the neighbors with antivirals is engaged.

The Tcell receptor is the recognition device on the CTL surface and the processed viral peptides - now called "epitopes" are transported to the cell surface with the usual protein trash chute of the cell - after shredding it into 10 aa pieces in the cells protein shredders - the proteasome-  it gets packed onto the hepatocytes trash conveyor belt - the MHC class I molecules and out it goes to the surface and bang it is now recognized by the Tcell receptor of the CTls patrolling by and the killing starts.

These CTL actions and the local interferon gamma prooduction are only mildy proinflammatory. And they tend to reduce viral production quite effectively, thereby overall reducing and curbing tissue damage and ideally limiting and terminating the disease. This is the "good" immune response - highly efficient, little damage.


THE THERAPEUTIC VACCINES as tested/developed  by Intercell in Austria and Innogenetics in Belgium are basically  strings/ mixtures of HCV peptides/epitopes, selected for effectiveness and combined with a critically important second aspect : A local adjuvant, a substance that activates /alerts the denditic cells - see above- to be even more active in processing, instructing and endowing the specific figthers (CTLs) and also the  class II "helper cells" that further help in the activation and training process for the CTLs, enhancing their numbers and giving them wild "peptalks', riling them up, sharpening their weapons and helping them to reproduce even faster., so they basically get a license to help the above licensing process to maximum efficacy.

In the end therefore we "enjoy" a huge double amplification process in the adaptive arm of the immune system.

The vaccine provides in concentrated form  the most effective epitopes in the context of ancient "danger recognition signals " ( the "adjuvants"), that gets the licensing authority ( the dendritic cells)  itself up to maximum speed.

So these vaccines work by driving the anti HCV Tcell response to maximum efficiency, to fight the virus in a more effective, less proinflammatory way and to get the infection to a low or no level.

Unfortunately, thus far, they do not work very well as hoped. This is partly, because HCV has learned to strip itself of all or most of  these fancy recognition epitopes, so the trash can looks perfectly clean and the CTL moves on, with no antiviral action...

[Whrose]

this is the most excellent explanation...reads like a true war story i very much enjoyed.

"HCV has learned to strip itself of all or most of these fancy recognition epitopes"
would you please continue on how it does this. i might be confused in thinking it is because of the hypervariable surface proteins on the hcv molecule, but now i am wondering if you mean something else. and please in the fascinating style as above.

[Hepatitis Researcher]

The above was just a very crude introduction in the adaptive cellular immune events - to explain how these therapeutic vaccines work without introducing more harm than good as dointime wondered.

The failure of this excellent adaptive defense system is at the very heart of the fact that HCV is a chronic disease, why IFN and/or riba work or not work.

The virions are produced inside the hepatocytes and some of their proteins, structural and nonstructural,  are cleaved to small peptides  and processed as described above and transported to the surface together with other cell "trash peptides".
In the evolution of HCV it invents ( for each of its components)  a functionally ( for its own purposes= max survival) optimized protein.

These  proteins ( a certain portion of them)  will, upon been cleaved/split up in the above described proteasome contain some peptide pieces (now at the hepatocyte surface laying in the described groove of the MHCclass I molecule) that have the inherent capacity to bind very well to the incoming CTLs. Other pieces do not bind at all. Not enough sticky amino acids are contained within them.

Thus there are good and bad epitopes ( from the human perspective).

There are quite a few restrictions on being a "good"epitope ( peptide fragment). It must be cleaved properly, fit the trash can ( the class I MHC molecule on the surface in which groove it must be well stuck and fitting).
It also must have "sticky and outreaching"' amino acids in its middle portion, so as to atttach firmly to the CTL detection device ( the "Tcell receptor")

Therefore in the end only a few good epitopes exist in small viruses like HBV and HCV, that will do the trick for presenting to /binding/exiting our adaptive immune system.

The virus needs these peptide stretches inside its proteins like  eg you need the handle on your vaccum cleaner for optimum functionality.

But when special forces are around that destroy your house if they find a vacuum cleaner with a handle ( they only can see the handle with their special devices) , you might want to sacrifice the good handle for a lousy one, like made of tape, to escape destruction, and if push comes to shuff you might sacrifice even more functionality in the items that end up in the trash, just not to be seen. Better half or 99% crippled than dead.

Thus HCV with its incredible evolutionary power finds a way to change literally most all the important ( for presentation and recognition) amino acids needed in those critical epitopes.  It is called epitope mutation and "epitope escape mutations". So it is less fit ( only one leg now, two fingers and no more tongue) but so what if you can have a trillion kids a day, you can settle for less offspring for a while, even when you are down to only 30000 a day, under IFN and riba - HCV often prevails in the end, after month of incredible hardship existence and crippled beyond recognition - literally. Pun fully  intended.

When the army is called back to regular medium duty - after IFN has stopped - HCV can return to a more comfortable lifestyle, regain a leg and a lousy tongue.

It is just that this pesty ribavirin is causing so much frantic adaption, that the beleagered HCV might overadapt and oops, creates a recognizable epitope again - on comes the merciless CTL - and the neighbors HCVs , despite  being much more careful, die also, because of the widespread spraying with local antivirals...

[geterdone]

Hi! hope everything is well, head still spinning from all the info but zeroed in on the first example.

I have a question, and it pertains to the (HP) Hydrogen Peroxide. It has been posted before about sores at the corners of the mouth and mouth sores in general during TX. I had googled it and found that the body naturally produces it but could not find any correlation between HP level being raised during the use of INF and RIBA. Could it be possible that the HP levels be raised during TX in a higher concentration and localize area to cause sores of the mouth and lips, like cracking corners of the lips? Like when you use HP in the mouth for a gum infection and it peals away the top layer of mucus membrane I guess, but if in a concentrated area under the surface of skin would it not have to release because the body can not absorb the higher level. I might be barking up the wrong tree here but had to ask.

Thanks!
Jasper

[Hepatitis Researcher]

Hydrogen peroxide, in contrast to other ROS (Reactive oxygen species) penetrates extremely well through biological membranes and is relatively long lived, as opposed to eg the Hydroxylradical.

For that reason, its production bu proinflammatory cells, like macrophages, is a very old and primitive, yet effective defense mechanism against intruding microorganisms, that want to replicate, It will inflict oxidative damage to the replicating DNA and to other delicate molecular components.Thus it is present in inflammatory tissue environments, acting as a microbicidal substance, but does damage to our own molecular machinery as well.

Hydrogen peroxide as a topical solution is used to treat , clean and desinfect local wounds or infected areas, like sores in the corner of the mounth, because it acts as a broad unspecific desinfectant that penetrates well - see above.

In an overall raised state of inflammation "readiness' as during tx, local stress causes localized tissue damage, like cracks etc due to the enhanced inflammatory response to any kind of injury. Hydrogen Peroxide, in this case produced as part of the inflammatory reaction is just one of several players that inflict the local tissue damage, but not to the extent that physical effects of the nature that you envison are involved. It does not reach concentrations of that magnitude.

[geterdone]

Ok, Thanks!
jasper

[Whrose]

wow wow YO riba!
you have given me more glue to put the pieces together. but i did smile as you describe your
explanation as crude.  for me the picture you described was a nice picture in which to begin to plug in the players in the TH1 immune response.

is there an exact place on the polyprotein molecule of hcv that those peptide fragments come from? perhaps E1 or E2, core, P7, or non structural areas? perhaps all? also do you have any idea of the function of the P7 area?  thinking that there are ~ 3000 amino acids in the hcv molecule are these epitopes random garbage from protein synthesis shuttled out from the cell, perhaps suggesting that this waste is random and not a deliberate survival mechanism characteristic replication of SS rna virus

also is it true that hcv also infects dendritic cells? has it been found to replicate in them or does it interfere as in HCV E2 binding to DC's . in this aspect it would surely cripple those CTL's? thus DC's are impaired to prime CTL's. also in my notes i have the core and NS3 protein inhibiting maturation of DC's.

how about IFNa? does it not also stimulate DC maturation? if HCV NS3 protease blocks activation of IRF3 then the this to would be another blow to cellular defenses.

gosh this just has to be one very clever virus! multi layered weapons to fight for its survival!

do you think it ever will be possible to develop an effective vaccine? can "a perfect epitope" be found considering the obstacles of its various immune disregulating abilites and RNA replication characteristics.

[mremeet]

Thanks for that fabulous description, what a read! We all really appreciate the time and care you put into explaining this stuff. Most of it is over my head, but some of it is actually starting to sink in. I like how you don't dumb down your responses too. Thanks again for sharing just a smidgen of what you've dedicated your life to.

[scratchinghead]

Yes, thank you. My mind was was hearing symphonies and cymbal crashes and strings and horns and Jimi Hendrix music while I was reading it.

[Hepatitis Researcher]

is there an exact place on the polyprotein molecule of hcv that those peptide fragments come from? perhaps E1 or E2, core, P7, or non structural areas?          perhaps all. IS CORRECT, IN PRINCIPLE


The proteasome - the "protein shredder"  of the cell, contains inside proteases that will chop a protein that is threaded into its inside at certain preferred  places. Thus it cuts all the viral proteins to pieces about 9 or 10 amino acids long, a lot of potential epitopes indeed.

But the vast majority, almost all and sometimes truly all, are not good, usable epitopes. Firstly they need so called anchor amino acids in the right place ( called "anchor residues") and of the right kind at the ends of the HCV epitope peptides in order to be firmly bound to the MHC class I molecule grooves  that will present them at the hepatocyte surface to the patroling CTLs. Thus if  the virus mutates the anchor amino acid in one otherwise good epitope - its now goodby to presentation/recognition.

What complicates this aspect is that each HLA tissue type binds different types of epitopes, thus a good epitope for your coworker might not work for you at all. ( Different MHCs, so that a portion of the population will stay alive in case of an epidemic, by using other epitopes - a strategic defense of man/animal  against microbial epidemics)  

Then as mentioned above, the middle portion of the epitope peptide has to contain special sticky amino acids of the right size/kind  to fit the need to attach firmly to the CTL Tcell receptor, there are limited opportunities and a single mutation here will abolish the binding -again good by recognition/protective effect.

So while the "waste peptides" originally were random, the virus smartly adapted their critical functional aa sites  so as to avoid any "good" epitopes.


"also is it true that hcv also infects dendritic cells? has it been found to replicate in them or does it interfere as in HCV E2 binding to DC's"

Well, dendritic cells certainly catch and swallow viruses for a living. How elso could they chop them and present them to prospective Tcells. But as you may have expected, they are quite resistant to any detrimental effects of the virus on their interior workings. But the virus has to produce his nonstructural proteins in the DCs in order for them to chop and present them. Its like you swallow a spider and let him lay his eggs inside you so that you can taste them and then show them on your tongue to the egg catching brigade - nasty stuff indeed.
However, HCV will try to evade this presentation by inhibiting its translation inside the DCs and also the further processing and transformation process

Whrose " i have the core and NS3 protein inhibiting maturation of DC's."  

that the DCs undergo to prepare for their great moment in live:
to hand out all these licenses to kill to the young naive Tcells waiting in line wanting eagerly  to become CTLs  and have the fun of reproducing itself to the multimillions... Sadly, only a rare few of these young eager lymphs will have that stimulating opportunity...

"how about IFNa? does it not also stimulate DC maturation?"  Of course a critical part in the global complex  cellular activating crosstalk that takes place at a viral infection. And HCV tries its best to block all these mechanisms wherever it can.

But note this is not part of the epitope evasion mechanism. It is part of the direct protein acrobatic of HCV that can have sex and eat at the same time it opens the door and throws lassos at the feet of soldiers hunting it.

But here it starts to arrive at a limit, whenever it removes an amino acids from an epitope it might also loose some of its complex selfmaintaining/defending capacity that was depending on that very amino acid to be in place. And riba will accelerate that adaption to the point that it starts overadapting, making mistakes...

A Tcell vaccine can certainly be designed, but it will not protect as well as a neutralizing surface B-cell epitope seeking antibody vaccine.
Because it only comes into play, when the virus gets processed in the above detailed ways. It does in principle not work to block intact virions.
But on its slow way into the body during "natural infections" ( as opposed to transfusions, IV transfer ) like sex, oral contacts, cat and kid scratching and  affectionate biting etc  there are many opportunities for the Dendritic and Tcell immunity to get activated in time and to block it on its way inside in  a local  lymph node. See the paper mentioned in the other thread regarding the Egyptian paper re Cell Mediated Immunity in household members. This mechanism is quite effective and amounts to a "life vaccination",  constantly refreshed by mild boosters, so HCV never reaches the liver and never reaches a level where antibodies are produced against its internal components - which requires a more massive infection. But the T cells of such a person react nicely when exposed to HCV peptides and happily produce gamma interferon in the laboratory when so specifically stimulated. You can tie them to a surface and they spit out the gamma inteferon that you catch locally and then make visible as a pile of gamma Interferon surrounding a stimulated T cell. Or you can send them one by one through a flow cytometry cell where a laser beam makes them glow up with fluorescence when the have the fluorescent labeled gamma interferon antibody bound to internal gamma IFN that they produced in response to these specific HCV peptides and nothing else...So you can prove that HCV was in this body, was expressed and caused a Tcell response, despite a negative HCV antibody test and of course a Zero VL PCR.
I hope DD reads this, this will make the Egyptian paper more clear and also it shows the way how to potentially test if a family member actually got "infected" that is NEG for AB and HCV PCR.

[Forseegood]

youre making my brain hurt again...lol...maybe if I read this in the morning - after I drink some green tea - I can make something out of it:)...I'm not hearing Hendrix like Scratchy, but this is really great though....to be able to read this over and maybe get the gist of it....Betcha you can't expound (as well as I can) about the post-war Italian Neo-Realism cinema of the 50's ....(forsee sticking her tongue out) sorry for messing up this thread with my immature drivel....won't be the first time...

[Hepatitis Researcher]

post-war Italian Neo-Realism cinema of the 50's ? Of course, that was the time when the Italians started to strip every tourist of his purse , so they could afford the movie tickets...

[Whrose]

ROFL   this may be one of my favorite quotes from you (i am collecting) LOVE IT!

".....IT IS PART OF THE DIRECT PROTEIN ACROBATIC OF HCV THAT IT CAN HAVE SEX AND EAT AT THE SAME TIME IT OPENS THE DOOR AND THROWS LASSO'S AT THE FEET OF THE SOLDIERS HUNTING IT"

OMG this viruus may be better than any man on earth and certainly my husband, lol.
hey...maybe you guys can learn a bit from this... )o(  

[Forseegood]

touche....who says scientists are devoid of a sense of humor?...while we're on supposedly humorous scientific questions....one I always wanted to ask you...why does asparagus make your pee smell so funny? or my pee, whomever....can I ruin a thread or what? Now I'm going to the principal/s office for that one...

[scratchinghead]

I wouldn't know. I don't go around sniffing my pee. . . . .

[gauf]

Dang it Ang! I was waiting to see what happens on the battlefield when the Alinia tanks roll in!!!  Asparagus pee indeed. Sprinkle some "scoop away" on it before you eat it.

[gauf]

So Alinia is an antiviral that has an efficacy 2000x greater than Riba, right? So.... When the Alinia calvary rides in.... the epitopes' are toast... right?  No quarter given?  

[merryBe]

sign me up for the next 50 vaccines, I don't want anymore bugs loose in my body!!

reminds me of that cartoon movie with Keanu Reeves..A Scanner Darkly

but pea brain here.

peroxide gives me the willies ever sice the big "free radical" scare.

Besides, what about rebound infalmmation with that stuff? Always heard that was a problem.

[willing]

HR: thank you indeed for a such a great post - it gets my nomination for post of the year!. If you ever feel so inspired, please  post an equivalent one on the mechanisms by which the nonspecific immune response and its accompanying inflammation lead to stellate cell activation and fibrosis build up...

However, I'm going to argue  with "pesky ribavirin is causing so much frantic adaptation". It's not that I personally don't believe riba is an HCV mutagen, as Pawlotsky's article notes, that role is the one most commonly attributed to it. However if the "frantic adaptation" is real there should be evidence of it and those ~1600 sequenced clones of the NS3 and NS5A coding  regions apparently showed none. So, IMHO,  the possibility that the mutagenic effect earlier reported by Crotty is an artifact of in-vitro concentrations (100 micro molar and up) and that, at in-vivo concentration, riba's influence is due to another effect remains open...

can't resist tacking on a couple of   my pet speculative corollaries:

- SVR represents not eradication of the virus but development of vigorous class I and class II T cells to "all" (since svr is so durable) of the virus' reproductively fit variations

- the collective epitope binding configuration  that results from an individual's MHC/HLA  alleles plays a role in how easy or hard it is for the virus to hide it's CTL epitopes and develop "stealth" status. Thus one's genetic signature is a key determinant of whether the virus succeeds in rebounding at EOT.

Drofi : you had mentioned you were a statistician a while back as I recall. Any thoughts on how to tease out an estimate the tx induced mutation rate from the background polymerase error rate and experimental/sequencing error? One way of extending the Pawlotsky's group investigation that occurred to me is correlating nucleotide variation  with the protein's structure.  The structure of various domains of NS3 and NS5A are deposited (eg see pdb entries 1zh1 or 1dxw) . It seems likely that structure would influence the mutation rate. Overall I think those genbank depositions are way exciting: here's a real opportunity to see how the virus reacted to riba monotherapy and soc..

[merryBe]

I love all your analogies, trash cans. martians, and spraying the neighbors oh my!!

You really should write a definitive book.....let's not call it "HCV for dummies"....but "Something Catchy" (pardon the pun) might be in order  : ))))))))))

[scratchinghead]

You sound like a space ship captain.

And all I can say to all of this is: "Damint Jim, I'm an engineer not a doctor!"

[dointime]

What a great answer!  It does plug a huge gap in my understanding of the HCV / immune system struggle, although I'll have to read it a good few times I think.  I thank you so much as you obviously put a lot of time and effort into it for the benefit of myself and others here.  

dointime.

[Ginger12521]

WOW, what an outstanding way of explaining the battle of the immune defenses during an active HCV infection! I guess it's safe to say this is one very elusive virus.  
Thanks so much for taking the time to share this very important information.

Do you see promise with the use of these vaccines in combination with current SOC?

[Hepatitis Researcher]

If combined with SOC and the other means, it would probably push the SVR% rate up a few more percent. But remember it can only work on epitopes that it contains and that the virus has not stripped itself of. That is the critical limitation. Its main idea is to strengthen quality and quantity of the CTL response to the epitopes that it contains to a higher level than the natural infection provides. It amounts to an artificial  "infection" with a "virus" that contains nothing but critical epitopes. But if the so elicited CTLs have nothing to   find/recognize/react to    at the hepatocytes ( because the actual  resident HCV has mutated those very epitopes), not much is gained.

[merryBe]

Omy gosh, just noticed you now have a profile, but still can't be reached privately!! Darn!!

Can't tell you how glad I was to have plowed through this Vaccines thread, and I agree, your best work yet in my limited exposure time, especially as relating to the analogous aspects!

The timing could not have been more perfect, as I have some familial sway within our state legislature and the ways and means end of the health stick might come under some influence here.

So my question is, would you mind in any way if I were to use some of your material and thoughts to educatate our lawmakers, as I've been asked to testify before the state legislature which has so far been unable to override our governor vetos that would have funded education and perhaps some future research, as well as free testing to those who want it even.

To quote "HCV is at the stage now that HIV was in the early 80's". Our country wants to bury it head in the sand rather than face it's needed leadership role as it did with AIDS.

To quote another source, it's easier to get an insurance company to approve an amputation than to agree to give a diabetic insulin, and it's easier to get a liver transplant than to get aggressive/proactive treatment at the onset.

MaryB.

[apache1]

Had to bring this thread back up.
____________________________________________________________________________________
Quote from HR:
"Tcells waiting in line wanting eagerly  to become CTLs  and have the fun of reproducing itself to the multimillions... Sadly, only a rare few of these young eager lymphs will have that stimulating opportunity... "
_____________________________________________________________________________________
HR you talk about these cell as if they think, feel and reason, is this possible? or are you just helping us to understand...lol

HR your explanations, are by far, the most interesting and informative reading on hep c anywhere on this forum or maybe the net, imo.
It lets a mechanical engineer like me, with no medical training, understand the workings of the HCV war raging on in my body. Very interesting work you do HR.
Thank you

What do you think of the ChronVac-C therapeutic vaccine ?

apache

[geterdone]

No, Thank you for bringing this thread back to the surface again. These are very interesting discussions in the workings of the HCV virus and are something we have gotten away from here on the board. The new members might find it interesting to read these past threads to get a better understanding of how the battle raging inside and what is being done to combat the virus. For past treaters like myself who have forgot the many interesting facts of the discussions is worth rereading.

I also see that MH has implemented a related link at the bottom of the page (other related discussions) to help put the topics together for easy transition to the next topic.

jasper

[Dee1956]

Thank you very intersting
Dee