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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]."



15 Responses
Avatar universal
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
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.
Avatar universal
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!
Avatar universal
Could ya'll put that in English?? -;) for us newbies??  I agree with itzallgood.

Thank you
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 ;-)
Avatar universal
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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