Xenotropic murine leukemia virus-related virus: current research, disease association

George

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from Future Medicine

Xenotropic murine leukemia virus-related virus: current research, disease associations and therapeutic opportunities

Judy A Mikovits*1, Vincent C Lombardi*1 & Francis W Ruscetti*2
Author for correspondence


Despite the fact that xenotropic murine leukemia virus-related virus (XMRV) research is in its infancy, considerable attention has been focused on this recently discovered human retrovirus because of the surprising association of XMRV with two very different diseases: prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome. Like other retroviral infections, XMRV integrates into host-cell DNA and thus endures for a lifetime. Little is known about host-cell interactions, reservoirs of infection or the lifecycle of XMRV. Information on murine xenotropic viruses, as well as current research on cellular tropism and cis-acting glucocorticoid response elements, provides intriguing clues for viral persistence, mechanisms of pathogenesis and opportunities for XMRV as a diagnostic biomarker and therapeutic target in myalgic encephalomyelitis/chronic fatigue syndrome.

Need subscription to access anybody got one!?????:worried:
 

Stone

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Goodness! They want $60 for a one time article read. Can we chip in to one person so they can get the article maybe? Just an idea. Maybe if we wait a minute someone will post it on FB or something. *sigh* Good find!
 

jspotila

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Goodness! They want $60 for a one time article read. Can we chip in to one person so they can get the article maybe? Just an idea. Maybe if we wait a minute someone will post it on FB or something. *sigh* Good find!
Great find, George. Have a biscuit! *pat pat*

At least a couple people here have med library access, so we should be able to see this full paper soon (I hope I hope).
 

Esther12

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"Like other retroviral infections, XMRV integrates into host-cell DNA and thus endures for a lifetime."

Doh... there goes my highly speculative and utterly ill-informed guess-work. I thought it was possible XMRV could be fought off, and that would solve some of the problems surrounding a CFS/XMRV link.

I wonder how sure they are about this.
 

George

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Great find, George. Have a biscuit! *pat pat*

At least a couple people here have med library access, so we should be able to see this full paper soon (I hope I hope).
I asked a friend to get me a copy and he's going to. (yippy, yippy, yippy, wait. . . I hate yippy dogs!) but what I'm wondering is what I can post and can't. I know I can do a summary on it. Does anyone know how much can be ummmm, "quoted"????? Without getting into hot water???
 

alex3619

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Hi Esther12,

My best guess is tht XMRV can probably be fought off in the first 4-10 days of infection, after which it can only be suppressed not eradicated (it is now integrated into DNA). Completely eradicating retroviruses is a hot topic in HIV research, as has been noted on many PR posts. In time we will be able to eradicate it, but until then we will have to settle for suppressing the virus with drugs.

Bye
Alex

"Like other retroviral infections, XMRV integrates into host-cell DNA and thus endures for a lifetime."

Doh... there goes my highly speculative and utterly ill-informed guess-work. I thought it was possible XMRV could be fought off, and that would solve some of the problems surrounding a CFS/XMRV link.

I wonder how sure they are about this.
 
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There is no rule. There is generally allowable quote or reference for news purposes as long as there is attribution. I have asked my attorney the same question.... how much before it becomes plagiarism. He said there is no rule.

I suggest summarize whole thing and don't use same words. They seem very proud of their words.

Tina
 

George

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There is no rule. There is generally allowable quote or reference for news purposes as long as there is attribution. I have asked my attorney the same question.... how much before it becomes plagiarism. He said there is no rule.

I suggest summarize whole thing and don't use same words. They seem very proud of their words.

Tina
Got it and thanks Tina! Hopefully I will have it sometime tomorrow. I'll read through it at least twice and then do a summary.
 

akrasia

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prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome.


Hm. Just had a quick glance at the Science Express abstract. Only cfs.

Is m.e. mentioned in the full Science article? Or is this the first time Mikovits et al. are, formally, invoking myalgic encephalomyelitis? Anyone know?
 
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I reckon they are trying to stop the creeps from squirming out of trouble. They cannot then claim that they were never looking at this disease.
 

George

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Well, I just finished reading the article and it's just a really really nice summary of where we are to date. There are a couple of tidbits that I'm going to pick out and "quote" that either I've missed before or are just stated differently. There's no new news, sorry guys!
 

akrasia

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I know Judy routinely uses me/cfs in conversation but I think this is the first time, at least in my extremely feeble memory, they've used m.e in a paper. If it's true it's very significant. It reinstates the legitimacy and primacy of myalgic encephalomyelitis.
 

Daffodil

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i think you have 72 hrs in which to try to eradicate MLV infection in mice with ARV's, if i remember correctly. my guess is another 10-15 yrs before they can do it for HIV in humans...and XMRV probably gets into a lot more cells than HIV does, so i wonder if it might be even harder to eradicate. also, it is more in the tissues than the peripheral blood, which also might make it harder...?

i cannot believe they still don't know what it does in the brain..thats where 95% of my symptoms are.

sue
xoxo
 

George

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The Summary

Sorry that I didn't get on this sooner but there really is no "new" news here. It's a good summary thought. Plus the paper is in a "picture format" so you can't actually copy and paste it. So I had to type all of the quotes. (grins) It took me a while.

I don't have a date as to when it was written I'll see if I can find that else where. It's good to keep up with the lag between submission and publication. In general papers lag about a year behind but this is such a hot topic on so many fronts that it looks like 5 to 6 months is going to be average for a while.

The paper starts out just outlining the origins which we are all familiar with regarding it's isolation in Prostate Cancer in 2006.

Throughout the paper the term Myalgic encephalomyelitis/chronic fatigue syndrome or ME/CFS is used rather than CFS/ME. This seems to be a trend and we may want to ask the WPI why they have taken to identifying the illness in these terms. Changing to an ME definition here in the US could help our cause significantly.

"Currently, clinicians rely on two main diagnostic criteria:the 1994 CDC Fukua Criteria for CFS [12] and the 2003 Canadian Consensus Criteria (CCC) for ME/CFS [13]. A number of clinicians prefer the CCC because of its requirement for postexertianal malaise, a hallmark of ME/CFS. Unfortunately, because some of the symptoms required for the Fukuda criteria overlap with depression, and the Fukuda criteria do not require exercise intolerance for a diagnosis of ME/CFS, the composition of the patient populations studied by different clinicians may be at variance."
I've seen this written in several of Dr. Mikovits papers and originally thought that it was part of the effort to "play nice" with scientific community, meaning not directly saying that the negative studies didn't do the science correctly. However, I think I may have been looking at it from a purely patient perspective. Instead I think this may be an education of researchers getting into the ME/CFS XMRV arena.

In a very subtle way the WPI may be helping to remove decades of misinformation and provide quality information to new researchers coming into the ME/CFS/XMRV arena.

The paper also state the following information.

"Decades of research into the pathophysiology of ME/CFS has characterized the disease as a multisystem disorder, manifested by low natural killer (NK) cell numbers and function, innate immune activation and antiviral enzyme (RNase L) dysfunction. Klimas et al. reported a significant expansion of CD26-activated T cells in CFS subjects [15]. This multifunctional molecule plays a major role in the regulation, development, maturation and migration of the T helper and NK cells as well as in B-cell immunoglobulin switching. Moreover, abnormal expression of CD26 is found in autoimmune disease."
This certainly makes ME/CFS sound much more like HIV or HTLV. Which makes me respect my illness in a different way. Which I belive may have been her point.

In the next section on Association of XMRV with ME/CFS She states that

"HIV and HTLV-1 retrovirus infections are detected clinically by:

  • Serological detection of antibodies to viral proteins in blood
  • Detection of viral proteins by immunoblot
  • Detection of proviral DNA by PCR of DNA or detection of virus RNA by reverse transcription -PCR
  • Isolation of virus from cell culture

In our initial publication in Science [23] and follow-up papers [24,25], we demonstrated that each of these detection methods could be used to detect XMRV in the blood of infected individuals [21]. "
I was not aware of all of the methods described above as being necessary to detect these retroviruses. After looking back at the previous studies that have been release to date on XMRV and ME/CFS the only one to do all of these was the Groom et al paper. the CDC paper was the second most complete but it omitted isolating virus from cell culture.

She goes on to discuss detection methods that have worked citing many of the positive prostate cancer studies and ends this section with a list of research questions that remain to be answered. It was this list that made me realize that Dr. Mikovits was using this paper to educate the research community.

As such the paper is some of the best PR that the ME/CFS community has had to date. It changes the name and focuses the research community on the aspect of ME moving us farther away from the CFS moniker, it introduces the CCC as the main mode of separating ME/CFS patients from the population of patients who may have other causes of illness such as drug interactions, hormone imbalances etc. And it puts us on an equal footing with patients suffering from AIDES and Human T Cell Leukemia. Certainly a different place from where the CDC shelves us.

The next section deals with early possible pathogenesis hypothesis based on what is known about retroviruses as well as MLV's. I'm not sure if the hypothesis are still valid or if we have moved beyond this more simplified explanations. Partially because I'm not sure when this was written. It seems likely based on the works cited that it was late February or early March. However, there is no referencing to the Monkey Studies by Kline et al here so it could have been earlier.

"We hypothesize that XMRV infection of B, T, NK and other immune cells could cause chronic inflammation and immune deficiency, resulting in an inability to mount an effective immune response to cancerous cells or opportunistic infections, as seen in CFS (the only non ME/CFS reference). A potential therapeutic target is revealed by the cis-acting gluccorcorticoid response elements characterized recently in Stephen Goff's laboratory [41]. When cell lines were evaluated for their ability to sustain robust replication of XMRV, the hormone-responsive prostate cancer cell line LNCaP, produced from the lymph node of a 62-year-old man with metastitic prostate cancer more than two decades ago, was identified as a useful indicator line for the presence of XMRV. Significantly, LNCaP cells are defective in the RNase L and Jak-Stat interferon responsive antiviral pathways. Androgens were also found to increase XMRV replication in these cell lines [42]. Interestingly, prostate cancer and ME/CFS both have inflammatory and stress-related clinical and epidemiological components."
One thing that I have noticed recently and it may make no never mind is that cancer potential in both PC and ME/CFS is teased out from the neuroimmune aspects seen only in ME/CFS. I take it that there is a major divide within research circles that will only follow 'body' pathogenesis or 'brain' pathogenesis. I've noticed this in some HIV studies as well.

"The Hypothesis of XMRV-induced neuroimmune pathogenesis
Nothing is known about the events following acute infection by XMRV nor about the time or course of infection. Our hypothesis, shown schematically in Figure 2, is that the acute infection is met with a strong immune response (gray line), which decreases the viral load (green line) and perhaps silences the active infection (pink line). but establishes reservoirs in long-lived immune monocyte/macrophges [43], T- and B-cell populations [44] and dendritic cells [44]. Strss hormones and inflammation 9y-axis0 could possibly activate XMRV expression increasing reservoirs and dysfunction of infected cell subsets. Over time, we propose that chronic XMRV expression, increasing viral reservoirs and chronic inflammation could lead to immune deficiency and, ultimately, increases in the presence of envelope proteins (pink line) lead to neurodegeneration and development of disease (blue line)."
I'll try to get the graphic up but most of you are familiar with the X graph in HIV. You reach a peak viral load that overwhelms the host immune response. The only thing I don't understand about this is why the majority of patients would show gradual onset rather than sudden onset. I know I can give you the exact date that I got "sick" October 5th 2006 at 6:45 a.m., no joke. I never recovered from that moment in time. However, for me each year that I taught I lost a little more ground becoming more and more ill but still able to think at the same levels. After the Oct. 5th my brain never worked the same, energy plummeted to never return. I can check off every category of the CCC criteria.

It may be that since the paper is primarily written to educate researchers showing them exactly what they expect to see, a familiar HIV type X graph is the best way to get them involved. Or perhaps the hypothesis is a best guess starting point based on past science and well, everybody has to start somewhere. (grins)

A rather interesting tidbit that I found was regarding the replication cycles in HIV was the following

"HIV-1 infection and CD4 T-cell count below 200 cells/ul or, alternatively, the presence of at least one of the 25 AIDS-defining conditions, the great majority of which are sustained by other microbes" [45]. Herpes viruses are among the most frequent co-pathogens establishing infection with HIV-1, resulting in a vicious cycle in which each virus facilitates the replication, shedding and transmission of the other. Intersecting epidemics are known in which the disease caused by one virus facilitates the transmission and pathogenesis of the other. An example of this is the herpes simplex virus, which may have contributed to the spread of HIV in Africa, where genital herpes has been estimated to account for the 30% of HIV infections [34]

Similar intersecting epidemics can be hypothesized for the spread of XMRV. Chronic herpes virus infections such as Epstein-Barr virus, human herpes virus-6 and cytomegalovirus are document among significant proportions of ME/CFS patients. Should XMRV infection be shown to be necessary for the development of ME/CFS, diseases caused by herpes virus may ultimately be defined as XMRV-associated neuroimmune disease co-defining illnesses."
I'm really not sure if this is a hypothesis for the epidemic type outbreaks or just for the spread of the virus. What I find interesting is the fact that much of this interaction among virus' seems to be well understood within the research community but it's all rather new to me. It's a path I want to explore in my own research over the next few weeks, brain willing. (grins)

The possible therapy's section was short and just a rehash of anti-retrovirals that have been tested and the paper ended with a short conclusion that mentioned the recent countries excluding blood donations which confused me as to when the paper was written because this was a later bit of information.

Sorry that there wasn't anything new or exciting. But Dr. Mikovits is certainly doing her part to give an honest account of what ME/CFS really is and I find this pretty wonderful. I know I've read research papers in the past that have seemed to get many of the aspects of the illness wrong so this is a big step in the right direction I think.

Hope this was of some interest. Sorry it took so long to get it all typed up.
 

aruschima

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George,

thanks so much. I wish you would be able to get us the whole thing pasted...

"The Hypothesis of XMRV-induced neuroimmune pathogenesis
Nothing is known about the events following acute infection by XMRV nor about the time or course of infection. Our hypothesis, shown schematically in Figure 2, is that the acute infection is met with a strong immune response (gray line), which decreases the viral load (green line) and perhaps silences the active infection (pink line). but establishes reservoirs in long-lived immune monocyte/macrophges [43], T- and B-cell populations [44] and dendritic cells [44]. Strss hormones and inflammation 9y-axis0 could possibly activate XMRV expression increasing reservoirs and dysfunction of infected cell subsets. Over time, we propose that chronic XMRV expression, increasing viral reservoirs and chronic inflammation could lead to immune deficiency and, ultimately, increases in the presence of envelope proteins (pink line) lead to neurodegeneration and development of disease (blue line)."

I heard Judy talk about this hypothesis in one of her first interviews in Nevada Newsmaker. Really fits like a puzzle.

Anyhow, have to run (actually running is out, more like dragging), leaving to Brussel to see Dr.Meirleier again, after more than three years! Will test for XMRV, wish be luck !