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CROI: XMRV Easily Grows in Lymph Tissue/Does not replicate/no Immune effects

Cort

Phoenix Rising Founder
http://www.retroconference.org/2011/Abstracts/40826.htm

Paper # 216

XMRV Induces a Nonproductive Infection in Human Lymphoid Tissue
Marta Curriu1, J Carrillo1, M Massanella1, E Garcia1, B Clotet1, C Carrato2, J Blanco1, and C Cabrera1
1Fndn irsiCaixa, Badalona, Spain and 2Hosp Univ Germans Trias i Pujol, Barcelona, Spain

Background: Xenotropic murine leukemia virus-related virus (XMRV) has been associated with prostate cancer and chronic fatigue syndrome. In humans the virus has been found in a variety of cell types, including T and B cells, and in rhesus macaques there is evidence for viral replication in lymphoid organs, suggesting that lymphocytes are a target for XMRV. Histocultures of tonsils support productive infection with various viruses, including HIV and human herpesvirus 6. In this study, ex vivo lymphoid tissue was used to investigate the pathogenic mechanisms of XMRV.

Methods: Tonsils from 2 healthy individuals undergoing tonsillectomy were collected and cultured in small pieces (2 mm3) over gelfoam soaked in RPMI medium. Tissue blocks were left uninfected or infected with XMRV stock obtained from a 22Rv1 cell supernatant. Culture medium was replaced every 3 days. After 14 days in culture, both tissues were homogenized and cells were isolated. Viral infection was evaluated at different times in the cells migrating out the tissue and at day 14 in tissue cells by PCR, analyzing viral DNA. In addition, tissue cells were immunophenotyped by flow cytometry and the presence of envelope protein (env) was analyzed by Western blot (WB) using an antibody to SFFV env that reacts with all poly- and xenotropic murine leukemia virus.

Results: Seven days post-infection cells migrating out the tissue were positive for XMRV DNA. After 14 days of culture, tissue cells were also positive, confirming that XMRV infected human tonsil tissue in the absence of exogenous stimulation. Despite the presence of XMRV DNA, infection does not seem to be productive since tissue lysates exhibited undetectable expression of XMRV env proteins by WB.

Uninfected and infected tissues showed similar percentages of T and B cells. XMRV infection did not modify the percentage of CD3 (76 and 75% in XMRV+ and XMRV– tissue, respectively), CD4 (53% vs 52%), CD8 (39% vs 40%), or CD19 cells (3% vs 1%). A deeper analysis of T cell subsets showed that XMRV infection did not modify the nave/memory cell ratio, or immune activation markers, as evaluated by the expression of HLA-DR and CD38.

Conclusions: Our data show that XMRV could be integrated into the human lymphoid tissue cells although this process does not culminate in an explicit productive infection. In addition, this infection did not result in changes of T or B cells nor an immune activation, suggesting that lymphoid tissue could be a latent tissue reservoir in XMRV infection.

They were able to grow XMRV in tonsil cells in the laboratory without 'stimulating them' but the virus was largely latent; ie it was able to move from cell to cell pretty easily - it can clearly infect cells in the lab - but once it got into them it did not replicate nor did it affect the immune cells. The authors suggest that lymphoid tissue could be a 'latent reservoir'; ie a reservoir in which XMRV could hang and survive but not a place, at least under the conditions of the test, it could rally forth from and attack the rest of the body. (Presumably if the conditions were changed (hormone fluctuations) it might be able to replicate and spread through the body. thanks to MarkMC for pointing this out)
 

SOC

Senior Member
Messages
7,849
They were able to grow XMRV in tonsil cells in the laboratory without 'stimulating them' but the virus was largely latent; ie it was able to move from cell to cell pretty easily - it can clearly infect cells in the lab - but once it got into them it did not replicate nor did it affect the immune cells. The authors suggest that lymphoid tissue could be a 'latent reservoir'; ie a reservoir in which XMRV could hang and survive but not a place it rally forth from and attack the rest of the body.

Is this like herpesvirus infections, which exist latent in most of the population and only (seem to) reactivate when the immune system is impaired?

How does it "move from cell to cell pretty easily" without replicating? Why couldn't it rally forth and attack the body if other latent viruses can?
 

natasa778

Senior Member
Messages
1,774
does "undetectable expression of XMRV env" automatically mean non-productive infection? As opposed to simply inability to detect?
 

free at last

Senior Member
Messages
697
Ok so they belive it can infect cells, which is backing up the monkey studies but in human subjects is it not ? does this rule out a auto immune type response from the tissues it does get into anyone. And surely they attempted to activate the virus to see what would happen, i wonder if they tried this ? Sickof cfs made me wonder this from hes good questions
 

eric_s

Senior Member
Messages
1,925
Location
Switzerland/Spain (Valencia)
http://www.retroconference.org/2011/Abstracts/40826.htm



They were able to grow XMRV in tonsil cells in the laboratory without 'stimulating them' but the virus was largely latent; ie it was able to move from cell to cell pretty easily - it can clearly infect cells in the lab - but once it got into them it did not replicate nor did it affect the immune cells. The authors suggest that lymphoid tissue could be a 'latent reservoir'; ie a reservoir in which XMRV could hang and survive but not a place it rally forth from and attack the rest of the body.
Hmmm... when i first read the thread's title "does not replicate/no immune effects" i felt bad. Now that i read the post i don't really know what to make of it. These were the researchers of IrsiCaixa, it was reported they will present a biomarker for ME/CFS at CROI, so i would expect something a bit more spectacular. And there was a call for more donations to them, that i and many others circulated over the internet. In case they were asking me and others for money, so they can continue to study XMRV in ME/CFS, which sounded very promising given the reports/anouncements, when in reality they haven't found anything helpful, i would start considering to reclaim my donations. So i hope we will hear some more information that allows us to know what to make of all of this.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi, this is more information on something we already knew. I find it very interesting. There are probably many interpretations - here is one possible scenario.

Initially XMRV is a stealth virus. It infects then essentially goes dormant. What I would have liked to see is treatment of these samples with hormones that might trigger the XMRV replication cycle. At that point we might well see massive viral replication. I suspect that XMRV only triggers when the body is under extreme stress.

The other problem is this: is the cell line XMRV used in this specific experiment capable of complete replication? Has it been sequenced? It might be capable of integration, but be incapable of producing whole virus.

I also think the latent tissue reservoir hypothesis deserves further attention.

Possibilities, possibilities, but where are the answers?

Bye
Alex
 

Enid

Senior Member
Messages
3,309
Location
UK
One gets the feeling that all these studies add to the "jigsaw" ME. And all recent findings taken together build to the big picture - pathogensis.
 

SilverbladeTE

Senior Member
Messages
3,043
Location
Somewhere near Glasgow, Scotland
What if XMRV is as Alex said, a stealth virus
perhaps it will NOT activate until it detects stress hormones/inflammation response from a whole body (needs a large array of triggers), in which to "cloak" itself OR have immune system responses to use in the resulting "fracas" as it were, or utilize hormones for activation?
and thus, wil not be able, at all, to turn itself "on" in such seperate, tiny tissue samples?
 

Cort

Phoenix Rising Founder
Is this like herpesvirus infections, which exist latent in most of the population and only (seem to) reactivate when the immune system is impaired?

How does it "move from cell to cell pretty easily" without replicating? Why couldn't it rally forth and attack the body if other latent viruses can?

My guess is that the virus was eventually able to infect many of the cells in the culture. As I remember this is what teh WPI showed in one of their experiments. The env gene is on the envelope of the virus - their inability to find it in the lysate suggested XMRV had not fully completed viral replication - that was my guess. But how did they find it otherwise? I don't know.

I see Alex says

The other problem is this: is the cell line XMRV used in this specific experiment capable of complete replication? Has it been sequenced? It might be capable of integration, but be incapable of producing whole virus.
 

Cort

Phoenix Rising Founder
http://en.wikipedia.org/wiki/Env_(gene)

Env (gene)

From Wikipedia, the free encyclopedia

Env is a viral protein that serves to form the viral envelope.

So the env protein forms the viral envelope and it is called the Env (gene) as well for some reason...Whatever the exact definition the point is, I believe, they were unable to detect the viral envelope or coat...that's my guess.
 

lansbergen

Senior Member
Messages
2,512
http://en.wikipedia.org/wiki/Env_(gene)
So the env protein forms the viral envelope and it is called the Env (gene) as well for some reason...Whatever the exact definition the point is, I believe, they were unable to detect the viral envelope or coat...that's my guess.

Genes are codes for making proteins.

http://en.wikipedia.org/wiki/Gene

A gene is a unit of heredity in a living organism. It normally resides on some stretches of DNA and RNA that codes for a type of protein or for an RNA chain that has a function in the organism.
 
Messages
877
http://www.retroconference.org/2011/Abstracts/40826.htm



They were able to grow XMRV in tonsil cells in the laboratory without 'stimulating them' but the virus was largely latent; ie it was able to move from cell to cell pretty easily - it can clearly infect cells in the lab - but once it got into them it did not replicate nor did it affect the immune cells. The authors suggest that lymphoid tissue could be a 'latent reservoir'; ie a reservoir in which XMRV could hang and survive but not a place it rally forth from and attack the rest of the body.

This sounds like "SPIN" Cort. Saying that XMRV could not rally forth from and attack the rest of the body sounds like spin. Latent from the dictionary means: present and capable of emerging and developing.

See definition of latent from dictionary.

: present and capable of emerging or developing but not now visible, obvious, active, or symptomatic <a latent infection>

http://www.merriam-webster.com/dictionary/latent
 

Grape Funk

Senior Member
Messages
113
Location
USA
I would like to see what happens when they apply multiple herpes viruses and bacteria to the already infected XMRV tissue (or vice versa), something like the hormonal effects stated.
 

Cort

Phoenix Rising Founder
This sounds like "SPIN" Cort. Saying that XMRV could not rally forth from and attack the rest of the body sounds like spin. Latent from the dictionary means: present and capable of emerging and developing.

See definition of latent from dictionary.

: present and capable of emerging or developing but not now visible, obvious, active, or symptomatic <a latent infection>

http://www.merriam-webster.com/dictionary/latent

Got it - so it could possibly do that. Makes sense to me. I'll fix it.
 

omerbasket

Senior Member
Messages
510
If they wanted to talk about immune effects, why didn't they let the WPI and NCI to present their study which found evidence for XMRV causing immune dysfunction?
 

eric_s

Senior Member
Messages
1,925
Location
Switzerland/Spain (Valencia)
Those researchers (IrsiCaixa, Spain), in December, presented immune dysfunction in ME/CFS. They did not say it is caused by XMRV and i think that was cautious and good. So now, i'm really waiting to hear some reporting about the presentations at CROI. It would be very surprising to all of a sudden hear from the same people that there is no such dysfunction in ME/CFS. That's not what the abstract says, but nevertheless, i'm curious and waiting. They have promised a biomarker, if i remember correctly and i think i do. And they have, at least indirectly, asked for our money. I don't want to spend my scarce money for research where the researchers already know there is nothing there to find, which would be the case here, since they asked one or two weeks ago. So i'm really waiting for information and hope the picture will make more sense in the end.

I'm really getting tired of waiting, "fishing in the dark", as we say here, being fed some crumbs every now and then, getting disappointed, always depending on other people that we hope will provide answers or spend more money. F* that... seriously... It can't work like that.
 
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