Therapeutic Vaccine Targets HCV

[Ginger12521]

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/

[Dee1956]

Thank you very intersting
Dee

[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

[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

[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.

[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.

[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?

[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.

[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!"

[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  : ))))))))))

[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]

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.

[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?  

[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.

[scratchinghead]

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

[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...

[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(  

[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...

[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]

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.

[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.

[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.

[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.

[geterdone]

Ok, 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.