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HCV found in Brain Autopsy

Sorry if this was already posted.

http://www.hcvets.com/data/hcv_liver/brain_dysfunction.htm
"We have recently identified the brain cells harboring HCV as macrophages/microglia [47]. In that study, basic brain cell types (macrophages/microglia, neurons, astrocytes, oligodendrocytes) were separated by laser capture microscopy from autopsy brain tissue from two HCV-positive patients. HCV-RNA positive and negative strands were consistently detected only in CD68-positive cells (macrophage/microglia). In a different approach, brain tissue was stained with anti-NS3 monoclonal antibodies, NS3-positive cells were separated by laser capture microscopy and phenotyped by the amplification of cell-specific transcripts. Again, the evidence pointed to CD68-positive cells as the being infected by HCV.

The hypothetical route for CNS infection could be provided by infected macrophages/monocytes, and perhaps also by B cells and T cells ('Trojan horse' mechanism). Although it was long believed that circulating leukocytes are excluded from the CNS, it is now known that all basic groups of leukocytes, T cells, B cells, macrophage/monocytes and natural killer cells, have the ability to enter the brain under certain conditions [55]. Importantly, certain monocyte family members are constantly being replaced as part of normal physiology [56,57], whereas the entry of T cells and B cells appears to be dependent only on the activation state of the leukocyte and not on CNS factors [58,59]. In support of this hypothetical mechanism come observations on the presence of HCV in the cerebrospinal fluid (CSF) from both HIV-positive and HIV-negative patients [60,61]. In a more recent study [62], we found HCV RNA in the cellular fraction of CSF (eight out of 13 patients), but viral sequences were rarely present in supernatants (two out of 13 patients). Importantly, in half of the patients in whom viral sequences were amplified, the CSF-derived virus was closer to that found in PBMC, than to that circulating in serum, which suggested that it was of lymphoid origin. In two of the latter patients sequences recovered from CSF and serum were classified as belonging to different genotypes. However, they were compatible with the genotype present in PBMC. These findings strongly suggest that the virus found in CSF was derived from peripheral blood leukocytes, and not serum. The presence of differing viral genotypes in serum and lymphoid compartments was also reported by others [23].

The still hypothetical scenario connecting HCV infection and functional CNS changes could be summarized as follows. HCV can infect PBMC, particularly macrophages, and this process is likely to be facilitated by concomitant HIV co-infection. Infected leukocytes could cross the blood-brain barrier ('Trojan horse' phenomenon) in a process similar to that postulated for HIV-1 infection [63,64]. Subsequently, there could be a secondary spread of HCV to permissive cells within the brain. The primary targets are brain microglia cells, which are essentially tissue-resident macrophages of blood monocytic origin [65]. Infected macrophages and microglia cells could release proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, neurotoxins such as nitric oxide, and viral proteins, which could induce an alteration in brain function leading in turn to neurocognitive dysfunction and depression [66,67]. A similar chain of events seems to be operational in HIV-1 infection [68,69]. However, despite some similarities there is a fundamental difference between HIV-1 and HCV infections, as the latter does not progress into AIDS-type dementia. This is perhaps due to the fact that HCV replication in macrophages is low level and is confined to a limited number of cells [28]."



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This is powerful stuff!  Everyone should read this article.  It explains many 'grey areas' regarding HCV, and also demonstrates how someone can carry two different genotypes, in different cells.  It also can be looked at as a sensible explanation for extrahepatic symptoms, rather than the old, tired explanation that they are a function of liver damage, or viral load, etc.  If the brain, CNS, spinal fluids, PBMC's, Lymphatic System, etc. are all infected at a cellular level, in addition to serum, then we have a vastly different virus on our hands than the HCV docs would have us believe.

Thanks for airing this article, and please lets have some comments from our members on the ramifications of what is being described.  This is the cutting edge information that we need to understand, and explore!!!  Let's keep it alive.  I think everyone should read and reflect on this article.

DoubleDose
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148588 tn?1465782409
Still a lot of speculation but at least the research is going in the  right direction.
If I understand this correctly, we're still talking about incomplete or altered RNA sequences, meaning no one has yet found the exact 9030-9042 g1, 9063 g3, or 9099 g2 sequences of nucleotides in any of these priveleged compartments. The changes the virus has to make to cross these barriers still, apparently, make it a one way trip and serum SVR is durable.
Most important and interesting to me is the fact they're starting to understand some of the mechanisms by which the CNS is actually effected.
Thank you for the article.
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Yes, I agree this article is very important. but i only understand some of it and in order for it to be discussable, it has to be a little more broken down.... so could you be so kind as to paraphrase it somewhat... what this is saying may change how we decide about undergoing treatment.  Thanks!
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Could ya'll put that in English?? -;) for us newbies??  I agree with itzallgood.

Thank you
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148588 tn?1465782409
It's been known for quite a while that most (85-90%) people who clear the virus from their blood stream still show signs of HCV RNA in the 'compartmentalized' systems of the body - spinal fluid lymph system and such. This includes people who clear on their own and those who do so with the help of interferon. HCV RNA is the stuff hepatitis virus is made of and is composed of nucleotides - between 9030 and 9042 depending on what kind of genotype one you have, 9063 for geno 3, and 9099 for geno 2. The virus reproduces by 'unzipping' its ladder shape and forming a negative image of itself then reforming off this negative template.
The HCV RNA that has been found in the compartmentalized systems is recognizable because it has enough of these 9000 or so nucleotides that it couldn't be from anything else, but *as far as I know* no complete strands have been discovered yet. The stands found have been both the negative and positive forms, showing that the virus is reproducing. This article speaks of exactly what part of the brain is effected and how.

Now, if I misunderstood or misexplained it, could somebody put it into simpler English for me ;-)
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thank you for the translation, now the question i have is, what is the implication for us with chronic hepc?  too early to know it sounds.  should we be looking for the effects of hep c in organs other than primarily the liver to determine treatment?  is this possible yet or practical? LOL  (PS i love the analogies like the zippy ladder, it makes a picture in my mind and i can grasp it better.
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More quotes from article above:


[7]. Extrahepatic sites of HCV replication may play a major role in viral persistence: it was recently demonstrated that the virus may linger for years at extrahepatic sites after ostensible successful treatment-induced or spontaneous clearance [32,36]. Furthermore, extrahepatic variants were demonstrated to have a low rate of non-synonymous mutations in the hypervariable envelope region, which may suggest low immunological pressure or low replication turnover, both of which could be conducive to viral persistence [23].

and:   In a recent study, we detected negative-strand HCV RNA, which is a viral replicative intermediary, in autopsy brain tissue of three out of six HCV-infected patients, and in two of these patients there was evidence of viral brain compartmentalization as viral sequences amplified from the brain differed from those circulating in serum. Importantly, brain-derived HCV variants were found to be more closely related to the virus present in the lymphoid system than to the virus circulating in serum, as based on sequence analysis of two different viral regions [53]. A close relationship between the HCV variants present in brain tissue and those present in lymph nodes was recently reported by another group of researchers [54]. Moreover, CNS-derived 5′-untranslated region sequences were reported to have reduced translation efficiency compared with virus present in the serum and liver. The latter finding is compatible with a slow replication rate of brain HCV strains and could perhaps favor viral latency.

My Comments:
All pointing to the potential for the virus to live and reproduce, albeit slowly and at lower levels, in other cells and tissues.  The brain, lymphatic system, CNS, spinal fluids, nerve pathways, etc. all seem to me to be very important as far as their potential to be the real cause of our physical and mental complaints relating to the infection.  Now if they continue to find these same reproducing viruses in these organs, systems, and cells, AFTER SVR, then we would have a vrey viable explanation for the long term problems many seem to experience after SVR (in addition to those caused by interferon, possibly), and a reason why those who also have 'spontaneously cleared ' the virus (taking no interferon whatsoever), also seem to suffer similar longterm complaints, in all the research that I have seen regarding their health.  

Think for a minute about the 'spontaneous clearers' and what they represent.  They are a great comparison point for SVR's because they are also now c"PCR negative" but never did any of the tx drugs to achieve that result.  We should be able to compare their longterm outcomes, with that of the SVR's to see whether all the HCV problems and sx fade away in either group, and just what the differences in outcome are, with interferon use, and without.

The studies I have read describing the health of 'spontaneous clearers' seem to indicate chronic fatigue, joint and muscular pain, brain fog, and cognitive issues as the prominent ongoing complaints, many years after clearance.

Maybe the article gives us the underlying reasoning for these odd results!

DoubleDose


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Thanks DD and desert for breaking this down a bit for those of us who don't have the backround or smarts to process it all, but most of us do have at least enough to grasp some of the info, but I really do appreciate all you guys/gals that are way ahead of the game and take the time to pull us along.

I have an interest in how hep c can and DOES affect the brain because as some of you may know (if you have read any of my posts) for about 1 year or 1 and a half (before hep dx) I have had a static noise in my right ear. Went to ENT and after googling and googling I said I think it has something to do with my brain - I thought it was an Acoustic Neuroma. Well he gave me this big grin and then laughed at me and said they were so rare and so on. Wouldn't give me an MRI. Winds up told my PCP and he didn't really pay attention to me. This problem is not a constant. It is noise induced. But then one day I was upset about something and I the side of my head felt weird and my ear started with the static noise when I spoke. I then told my PCP that I now thought it was something to do with the blood vessels in my head. He said, "well what if it is?" There won't really be anything we can do etc. I said but I think this has something to do with the hep c. Winds up just recently he asked besides the hep how am I feeling. I told him that when the static thing happens with my ear it concerns me. So I did get the MRI finally and it showed changes in white matter that may reflect small vessel disease. He didn't think anything of it,and when I did ask him at the next vist he said  people as they age can get this. But here's the thing. I'm 53, in good shape and other than hep no problems (thank God). So now I decide to google about hep and small vessel disease and there was some info, but it seems not enough known yet, BUT since research is that much more advanced with HIV, I started looking at that. Even with my limited ability to understand everything I read concerning this, it is in black and white that HIV does affect the brain (as most of us already know. )Aids related dementia is proof of the pudding. As far as the above study mentioning cognitive dyfunction and depression, there is no doubt in my mind that the longer we carry this virus (which will probably be 'forever' if you count the lymph etc) we will struggle more than those without hep with mood problems/depression. The thing I disagree with as far as this study above is when they mentioned that with the hepc found in brain it wouldn't progress to dementia as does the Aids related. Sorry but here's where I believe these scientists prove they lack logic. Small vessel disease can lead to dementia and if hep c can cause SVD as it does with HIV patients, why wouldn't it cause dementia in hep patients? Well maybe it would not happen as quickly, but there is a possibility it will happen as far as I am concerned.Sorry to sound so gloomy. I don't mean to come across like that. I plan on continuing to do all the right things to keep things in check, healthy diet, supplements (especially fish oils etc) and eventually just give it ALL(not just little bits and pieces) over to God - cause He can work it out. But getting back to my  long boring story.........

I showed my NP my MRI and she agreed with me that what showed on my MRI might be from the hep. She said the hep can affect the CNS, which at this point I already knew.

I have been experiencing numbness and tingling in my fingers hands, tongue lips started about 4- 5 week post tx. Before that it was only my thumbs that would not feel right mostly the right thumb if in the cold. As of recent I don't have tingling in my lips anymore - thank God.I didn't have this when I had my 4 week lab so didn't tell the NP or doc at the 4 week post blood test.

I asked if it would be a good idea to see a Neurologist. She said yes. I told her I would want a Neuro doc that has seen the brain MRI's of hep c patients, but it seems none to be found but she mentioned a Neuro doc that has alot of HIV patients,,,here's the thing...it seems none of these hep docs are including MRI's as part of an examination when it comes to hep C. I am going to a leading hepatologist, so if brain MRI's were part of the ticket, I would have had one without asking. Okay what is my point?? None of the doctors are quite up to par with what they should be doing as far as hepC IMO. If these doctors continue to wait for studies to end before they dig a little deeper, we will be waiting a long time it seems. Granted some GI's really believe hep C is a locked up in our liver as a prisoner, but the other doctors that believe that Hep does affect the rest of our body...how about running some more tests and lets see what's going on?

It's up to us, the ones affected and infected by this virus to continue to bring information to our doctors and INSIST they listen. I'm maybe a little bit more fortunate because my team is ahead of the game but there still is that attitude of when you SVR the struggle is over and Hep C is behind you.

It amazes me some of the things I have read on forum( the impression doctors give their patients) - that SVR means the fat lady sang her song..some doctors say.."you're SVR, go start a family." Yes of course people who want to have children I can understand that. BUT these same doctors that will not listen to our post sx because they haven't heard enough post tx complaints or seen any studies to prove our complaints, tell girls its okay to become pregnant and all will be okay. How do they know all will be okay?Where's the study that they always rely on? Interferon combined with riba has only been used 7 years, correct? Maybe I am wrong, but anyhow, do you get my point? If anything, these doctors should tell these women, "there hasn't been any studies yet for me to tell you whether after taking these drugs it would be safe, so go and start a family BUT  I can't tell you it is without risk - possibly next generation." Remember DES? That was supposed to be safe, but next generation problems showed up. If anyone is still with me, I am just venting because I am sick of doctors telling people some of these post sides "are in their head," as if we are making them up. Well bingo, they are in OUR HEAD because hep DOES affect our brain. I don't need to see anymore studies to believe it. Any doctor who keeps up with the studies are aware that hep c crosses the BBB. LOGIC would tell you for that reason alone, lets have some more studies PRONTO.

PS. One other person on forum had a brain MRI that I know of. Hers also showed some abnormalities. Maybe some of you guys should push for a brain MRI. If we see others on forum that have abnormalities and we gather all of our info maybe it will help if we show our doctors, but first check out an article posted by a member on forum concerning the contrast used with MRI's and possible effects on those who have chronic liver disease or kidney disease before you deceide. I think its more of a worry for those with kidney, but who knows. My NP didn't think the contrast was something to be concerned about and I'm not at this point.

Sorry for the rambling on and on, but who else will listen when we get in these moods.Even if you don't listen I can pretend someone actually read the entire boring post and I will feel better because I had a chance to vent.
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I really appreciate your reply, and agree with you completely.  The doctors are very superficial in their consideration and follow up of post tx problems, HCV's effect on other areas of our bodies, CNS relared disorders, autoimmune, etc.  They are still 'latched on' to the philosophy that HCV is a blood/ liver virus, and is 'eradicated after SVR, cured!.  All of these assumptions are currently proven incorrect by almost all research, and many other branches of medicine already recognize the infectivity of HCV in other compartments and organs, as well as its ability to live in a low level almost invisible state after SVR and spontaneous clearance.,  

There is unbelievable foot dragging in looking at extra hepatic symptoms and the relationship to HCV, post-tx problems and why they exist, brain related dysfunction, CNS problems, etc. , etc.  The doctors seem to use their own quick and easy logic in dismissing many of these issues.  Its easy for them to 'assume' that all the problems are from things like lingering immune system over reaction, aging, the body reacting to old inactive 'particles' of virus, liver dysfunction, anxiety, depression, etc. etc.  Its either in our minds, or our system is 'playing tricks on us'.  All silly assumptions with no investigation or research to back them up.  

The real research points entirely in a different direction!  HCV infection in a wide variety of organs and compartments, HCV remaining long after SVR and reproducing, and a wide range of demonstrable changes in brain, glandular, and nervous system physiology and function in those with HCV or those previously infected.  Let's hope these research studies incresase in number and scope, and that the mainstream doctors start reading them!  They really need to be a part of this process.  We will never find the answers and treatments without their joining the party.  If they keep saying nothing is wrong, and we are all cured...we are in for a LONG, LONG wait.

DoubleDose
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thank you for sharing your story, i believe it will help many others or are experiencing EHM of hcv.
there was another interesting article on hcv and neuropathy on the vet site you might find interesting.
http://www.hcvets.com/data/hcv_liver/neuropathy.htm
i am sorry to hear your symptoms were brushed over by your doc, and yes you are so right to say there are very few and far neurologists with understanding in hcv neuropathology and unfortunately they are the specialty that should be able to help this uncommon EHM. *please share with us should you find one.* once more i feel our hepc docs are failing us when those of us present with neurological sx or other EHM do not give us the proper referral for help as the current literature for  hepc in extra hepatic compartments is evident.
i have read of these kind of sx associated with MC and also success and relief after INF/riba tx.
i hope and pray this is true for you!  a big salute to your courage and persistance to find out the truth and challenge your docs to listen!
i welcome your vents as i think you are speaking for many of us!  

i have to make one statement about medical treatment. we all should be informed pateints and realize that present technology however advanced is limited and the understanding today will indeed be different in years to come with new advances and research.  while it is not a perfect system," the hopes and advances of yesterday have become our realization, and there are many in the future that will benefit from our today".



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I think one of the principal problems is that hepatology is a branch of gastro-intestinal medicine ,and these docs are very specialized.  Most of medicine is nowadays.  And our primary care physicians are being utilized as gate keepers, with jam-packed schedules, so they - who really are the ones who should be coordinating a holistic approach to patient care - just don't have the time.  Yes, we have to really push this issue and insist that somebody pay attention.  Easier said than done, but I do think it's partly up to us.
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DD,,, thanks, glad you appreciated my reply. Sometimes I delete things before I actually hit the post button because I know I am too wordy and my brain doesn't have an edit mode - nothing to do with EHM. I've been like this for years- just talk too much.

Please also read what I post to Whrose (concerning teeth)

Whrose,, thanks for your kind words and also for the article. I did read this one already, but I didn't know where I filed it so thanks. It did scare me when I first read it because IF I do have something such as inflamation in the nerves related to cryo or something, that concerns me. Lately at night my gums feel tingly on top of my other tingles in the fingers etc. I said to my husband (who is about ready to jump out a window - tired of hearing my EMC's ) "what if I am developing nerve damage in my gums from the hep and I lose my teeth?" He rolled over (we were in bed about to go to sleep) and said I will be fine. Poor guy, I'm driving him nuts with all this. But really Whrose, that is possible as far as I am concerned. So then I found this article, the same one you posted and it freaked me out because it mentions someone loosing their teeth!  But anyhow DoubleD mentioned his teeth seem to be getting weak and the dentist told him he doesn't have infection etc, so I wondered if it was from having EHM. So anyhow this stuff can get on your last nerve and for real. My teeth are in good shape and I don't want a problem starting with them. But anyhow I agree with your statement concerning medical treatment. Thats so true.

Nice talking to you. I will keep you posted. Hopefully my next post PCR is still UND and somehow I have to find someone who will do the cryo test correctly. I will ask my mothers Oncologist next week when I take her to him. Take care.

pigeonca..I agree with you 100%. Everybody is a specialist these days and it seems they know very little beyond what they specialize in. And the PCP knows a little of this and a little of that and not enough in what we need him for. I guess thats why at some point we have to just trust God. As much as I do believe in God,people such as myself- strong willed, opinionated, always wanting to be incontrol have difficulty letting go and letting God. There is a certain amount of responsibility we have to help ourselves get well, but then there comes a time where we must stop and just 'Trust Him." My problem has always where is the cut off point - where I have done my part and now its just to trust.Thats what I have to learn from all of this.
take care -good to talk to you.
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Thanks for the translations into English.  Pretty scary stuff.  Are  the viruses lurking in other parts of the body responsible for not achieving SVR, or do they know?  Are any of the medications capable of crossing the blood-brain barrier?
Are far as gastros and extrahepatic symptoms, I seem to have the same problems with mine as a number of you do. "You're only depressed because you have a chronic disease"  "You're upset about being tired (?) and I just had to tell someone they had end-stage cirrhosis"  That sounds so harsh - he did say those things, but he's realy great in all other ways.
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Ireally love the:  "You're only depressed because you have a chronic disease"

I have heard this a number of times, from top HCV doctors, and I really have to bite my tongue!!!!  Are they kidding?  The list of symptoms and illnesses attributed to HCV is as long as my arm, and to assume its because we are depressed over knowing that we have a disease is just as arrogant as you can get.

Besides that, I think about all the years that I did NOT know I had a chronic disease, and how many doctors I discussed my fatigue, and depressive symptoms with.  My symptoms truly came first, the knowledge of the illness many years (decades) later.  The doctors just don't know how much they don't know.

DD
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Are any of the medications capable of crossing the blood-brain barrier?
---------------------------------------------------------------------------------------------------
I think the Pegintron crosses over - someone will correct me if I am wrong. I was told pegasys targets the liver better tho. Who the heck knows tho.

It seems there are very few things that can cross the BBB. I am going to try and find what natural supplements can cross. I know green "tea" can cross BBB, so I am trying to drink alot of that. Since it does help with free radicals and won't harm us, I'll continue drinking it. It seems in pill form it doesn't cross the BBB. Studies with dementia due to aids it doesn't seem to help, but maybe with hep if the stray virons are weaker (just guessing) than aids virus, maybe the green tea would benefit us in some way. Who knows - can't hurt to try.

http://www.medscape.com/viewarticle/556087
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