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Proteins of the XMRV retrovirus Christopher Carter

pollycbr125

Senior Member
Messages
353
Location
yorkshire
http://precedings.nature.com/documents/4669/version/1

Proteins of the XMRV retrovirus implicated in chronic fatigue syndrome and prostate cancer are homologous to human proteins relevant to both diseases.


Received 15 July 2010 01:56 UTC; Posted 15 July 2010
Subjects:
Cancer, Immunology, Microbiology, Neuroscience
Tags:
xmrv virus chronic fatigue syndrome prostate cancer viral mimicry
Abstract:
The XMRV retrovirus has been implicated in chronic fatigue syndrome and prostate cancer. A homology search comparing retroviral with human proteins revealed short contiguous amino acid strings (typically 5-8 aa) matching human proteins whose dysfunction might be expected to cause fatigue, including mitochondrial proteins related to oxidative phosphorylation, glutamate receptors and their synaptic scaffolds, muscular acetylcholine receptor scaffolds and structural proteins, components of the immune system, and phosphatidylinositol signalling inter alia. Viral proteins are also homologous to members of the oestrogen, peroxisome proliferator, and CREB activated receptor networks, all of which are implicated in prostate cancer, and to a protein, SRCAP, that controls the expression of the prostate-specific antigen. These short matches are often predicted to be antigenic, and antibodies to XMRV proteins may target their human homologues. This is supported by the presence of autoantibodies to muscarinic receptors , vimentin and LAMINB1 (all XMRV homologues) in chronic fatigue syndrome sufferers. Homologous XMRV proteins might also interfere with the protein interactomes of their human homologues. Viral mimicry of human proteins is extensive and often relevant to disease. For example Epstein-Barr viral proteins aligns with multiple sclerosis autoantigens, while HIV-1 proteins align with several components of the immune system. Mutant proteins in Huntington's disease and cystic fibrosis also align with proteins from common phages or viruses. This suggests a common theme of viral derived autoimmunity/network interference in many human disorders, which could radically change the shape of future therapy. Such viral mimicry likely relates to the idea that life evolved from viruses, leaving behind a legacy of viral derived human proteins whose homology to the current virome may be responsible for many human diseases and syndromes. Vaccination programmes or immunosuppression may be beneficial in many of these conditions
 

Rafael

XMRV+ Member
Messages
66
Location
Ontario, Canada
Thanks for posting this.
I don't understand all the terms but my takeaway is:
- the findings increase the probability that XMRV is at least a co-factor in ME and PC.
- this is a nice vehicle for scientists to share pre-official-publication findings (if they want to, and aren't afraid of getting slowed down by too many questions)
- Another strong reason for greater research investment in ME: "common theme of viral derived autoimmunity/network interference in MANY human disorders, which could radically change the shape of future therapy"
 

gu3vara

Senior Member
Messages
339
I don't know about you, but at this point I just CAN'T believe anymore that CFS isn't caused by XMRV, the stack of scientific evidence is adding up. That's great for us!

I doubted about this whole thing for a while but recently I just have to admit it's looking pretty damn good now
 

judderwocky

Senior Member
Messages
328
I don't know about you, but at this point I just CAN'T believe anymore that CFS isn't caused by XMRV, the stack of scientific evidence is adding up. That's great for us!

I doubted about this whole thing for a while but recently I just have to admit it's looking pretty damn good now

Thinking of Jerry Maguire..... " You had me at retrovirus"
 

VillageLife

Senior Member
Messages
674
Location
United Kingdom
THE FULL PAPER

Proteins of the XMRV retrovirus implicated in chronic fatigue syndrome and prostate
cancer are homologous to human proteins relevant to both conditions.
C.J.Carter


The XMRV retrovirus has been implicated in chronic fatigue syndrome and
prostate cancer. A homology search comparing retroviral with human proteins
revealed short contiguous amino acid strings (typically 5-8 aa) matching human
proteins whose dysfunction might be expected to cause fatigue, including
mitochondrial proteins related to oxidative phosphorylation, glutamate receptors and
their synaptic scaffolds, muscular acetylcholine receptor scaffolds and structural
proteins, components of the immune system, and phosphatidylinositol signalling inter
alia. Viral proteins are also homologous to members of the oestrogen, peroxisome
proliferator, and CREB activated receptor networks, all of which are implicated in
prostate cancer, and to a protein, SRCAP, that controls the expression of the prostatespecific
antigen. These short matches are often predicted to be antigenic, and
antibodies to XMRV proteins may target their human homologues. This is supported
by the presence of autoantibodies to muscarinic receptors , vimentin and LAMINB1
(all XMRV homologues) in chronic fatigue syndrome sufferers. Homologous XMRV
proteins might also interfere with the protein interactomes of their human
homologues. Viral mimicry of human proteins is extensive and often relevant to
disease. For example Epstein-Barr viral proteins aligns with multiple sclerosis
autoantigens, while HIV-1 proteins align with several components of the immune
system. Mutant proteins in Huntington’s disease and cystic fibrosis also align with
proteins from common phages or viruses. This suggests a common theme of viral
derived autoimmunity/network interference in many human disorders, which could
radically change the shape of future therapy. Such viral mimicry likely relates to the
idea that life evolved from viruses, leaving behind a legacy of viral derived human
proteins whose homology to the current virome may be responsible for many human
diseases and syndromes. Vaccination programmes or immunosuppression may be
beneficial in many of these conditions.


Introduction.

Chronic fatigue syndrome is an unexplained medical condition characterised
by extreme mental and physical fatigue 25. and by cognitive impairment, depression
and muscular pain and excessive sensitivity to light, sound and smell 41. The condition
has a very high prevalence, for example a figure of 30% of the general population was
recently reported in a study from the Netherlands 46 and there are as many as four
million sufferers in the USA. 7 Perhaps most of the population will experience this
condition at some time in their lives. It may be triggered by infection or trauma or by
vaccination against hepatitis b 33 or against multiple infectious agents (suggested as
the cause of Gulf War syndrome31,49) . The syndrome appears to have an autoimmune
component and antibodies to silicone, squalene , muscarinic receptors and nuclear
envelope antigens have all been reported

The syndrome is treated by low dose antidepressants which are palliative at
best 48, has been considered as a psychiatric phenomenon 47 and can indeed benefit
from cognitive therapy 49. The lack of effective therapy has encouraged the use of
alternative medicine whose effectiveness remains to be verified by the scientific
community 49. Many studies have linked viral infection to the syndrome and
implicated the cytomegalovirus, the Epstein-Barr virus, human herpes virus 6 and 7 ,
hepatitis C, an intestinal enterovirus , the Nipah virus and parvovirus B19
5,10,11,15,32,42,49. Microbial infections are also common in these patients 52,
Perhaps the most intensively studied and hotly debated 21 viral cause of chronic
fatigue syndrome is the XMRV retrovirus (Xenotropic murine leukemia virus-related
virus) initially reported by Lombardi and colleagues 24. This virus has also been
implicated in prostate cancer 4. As shown below, this virus expresses proteins which
are homologous to several human proteins which are relevant to all of the symptoms
encountered in chronic fatigue syndrome and to the proteins implicated in prostate
cancer.

Methods

A homology search between the XMRV genome (NC_007815.1) or the
XMRV proteins and human proteins (blastx; nucleotide search vs proteins or Blastp;
protein vs protein) was undertaken using the NCBI server 2. Only proteins with
matches containing pentapeptide strings were included, except in the case of longer
strings with few gaps or where several contiguous strings were identified. The results
in Tables 1-10 record the position of the match within the viral genome or viral
protein and the position within the matching human proteins, (whose DNA will also
evidently match that of the viral genome) Accession numbers and a brief definition
of function, as recorded in Entrez gene are provided. The B-cell immunogenecity of
different amino acids was calculated using the B-epitope prediction server (Bepipred)
23 http://www.cbs.dtu.dk/services/BepiPred/
and high scoring amino acids are tagged (*) in the various tables

Results
XMRV proteins are homologous to a variety of human proteins as shown in
Table 1-10. Perhaps the most relevant in relation to fatigue are the mitochondrial
proteins involved in respiration and oxidative phosphorylation (eg ATP801, COX11)
(Table 1, Fig 1). Glutamate is the primary excitatory brain neurotransmitter and
XMRV homology to the AMPA receptor GRIA4 and to members of the presynaptic
(Bassoon, piccolo) and postsynaptic machinery (DLGAP3)might also contribute to
cognitive defects (Table 2, Fig 1) as might members of the phosphatidylinositol,
phosphodiesterase and Rho signalling networks (Table 3, Fig 1).. The muscular pain
experienced by chronic fatigue sufferers might well be related to homology with
proteins involved in acetylcholine receptor scaffolding (Table 2, Fig 1) and to
structural muscle elements (Table 4, Fig 1, and the sensitivity to smell to homology
with several olfactory receptors (Table 2 , Fig 1).
XMRV proteins are also homologous to proteins of the growth factor signalling
networks (e.g. tyrosine kinases FLT3 and TYRO3) (Table 5) which are relevant to
cancer-related growth (Fig 2)


They are also homologous to the TAP1 and TAP2 antigen transporter and to a number
of immunoglobulins and cytokine-related proteins (Table 6, Fig 2).
Other classes involved include a number of proteins related to nuclear receptors,
several of which (oestrogen and PPAR receptors and CREB) are directly implicated in
prostate cancer 6,30,50, and to a protein (SRCAP) that controls the expression of the
prostate-specific antigen the 39 ,marker for prostate cancer (Table 7, Fig 2) . Other
homologous classes include transcription factors (Table 8, Fig 2),adhesion molecules
(Table 9, Fig 1 and 2) , proteases and protein processors (Table 11) and a number of
miscellaneous or unknown proteins (Table 13).
Some of the viral translated genome matches to human proteins do not appear
to relate to any known XMRV protein (certain olfactory receptors the phosphatase
PPAPDC2 and the phosphodiesterase ENPP6). This may be related to viral open
reading frames that have not yet been characterised , for example a new ORF has just
been described for the cytomagalovirus 29 , or that may shift with mutation. However
in these cases viral DNA remains homologous to that of the human target.
Different amino acids have different antigenicity depending on their charge
and hydrophobicity characteristics and the B-epitope antigenicity index for each
amino acid is shown in Table 14 23. It should be noted that such indices can change
markedly depending on the number of amino acids in the contiguous string or on the
identity of the neighbouring amino acids. Marked synergy exists when antigenic
amino acids form contiguous stretches. This individual index serves as a rough gauge
of the antigenic potential of the peptide. The top 5 antigenic amino acids are marked
with an asterisk in the various tables, and contiguous antigenic amino acids, which are
the most likely epitope and cross-reactive candidates, are highlighted in grey. It can
be seen that a number of matching proteins are predicted to be highly antigenic.
These include the mitochondrial proteins CHCHD10 ,acetyl CoA carboxylase and the
sulfite oxidase SUOX, (Table 1), the glutamate receptor GRIA4 (Table 2) the TBCC
tumour suppressor (Table 7) numerous growth regulators (FLT3, TYRO3,WNT10B
and EIF4B ) (Table 5) the antigen transporter TAP1 (Table 6) the PPAR and
oestrogen receptor and PSA regulators, PELP1, PPRC1 and SRCAP (Table 7), the
transcription factor FOXO6 (Table 8) , pleckstrin 3 (Table 9) the metalloprotease
ADAMTS9 and ubiquilin 3 (Table 10).

Discussion.

The XMRV virus expresses predicted proteins with homology to human
proteins that are clearly highly relevant to the symptoms encountered in this disease,
including fatigue (mitochondrial respiration), cognitive deficits 49 (glutamate, PI
signalling) problems related to olfaction 41(olfactory receptors) muscular pain 41
(acetylcholine receptor and muscle related structural proteins) and the association
with many active viral and microbial infections 19 (immune related proteins).
.XMRV viral proteins are also highly homologous to components of peroxisome
proliferator-activated receptor gamma (PPARG) or oestrogen receptor signalling
networks both of which have been implicated in prostate cancer 6,30 A viral protein is
also homologous to SRCAP which controls the expression of the prostate specific
antigen, the cardinal marker of prostate cancer39.
Although these matching strings are short, they are often contiguous and the
viral homologues may interfere with their human counterparts in a number of ways.
Firstly, many of these stretches are predicted to be antigenic and antibodies to the
virus may also target the human homologues. Indeed autoantibodies to muscarinic
receptors, cellular cytoskeletal components, including vimentin and other Lamina
related proteins and to nuclear envelope proteins including Lamin A and LAMIN B1
have been reported in chronic fatigue syndrome 22,44. These were all identified as
XMRV homologues in this survey (specifically muscarinic receptor, CHRM2, Lamin
B1 and Vimentin and generally the cytoskeletal components in Table 4).
Viral DNA will also match that of the human target and possibly sequester host
transcription factors or microRNA of influence splicing of the homologous human
gene.
These homologies, targeted at highly relevant proteins support the implication
of the virus in both chronic fatigue syndrome and prostate cancer.
Several studies have failed to detect the virus in chronic fatigue syndrome and
the issue is hotly debated 14,21,28. Because the viral proteins are homologous to human
proteins, it is likely that any anybodies generated in response to the virus would target
their human homologues. This is supported by the high predicted antigenicity of a
number of viral matching proteins and by the presence of autoantibodies to viral
matching proteins in chronic fatigue sufferers. As the human proteins are persistently
encountered by the antibody, such an autoimmune response would become selfsustaining,
thus no longer requiring the presence of the virus. Indeed, the more
successful the immune response against the virus, the greater the risk of
autoimmunity, a disastrous pyrrhic victory. This scenario could thus explain the
failure to detect the virus in several studies.
It has recently been shown that Raltegravir potently inhibits XMRV
replication and clinical trials in chronic fatigue syndrome and prostate cancer have
already been proposed 38 a suggestion supported by the results of this survey.
However, it is possible that the effects of the virus, in the form of autoimmunity
persist after viral elimination and different strategies including immunosuppression
might be considered in such cases.
Viral mimicry of human proteins appears to be a near universal phenomenon.
For example several viruses (almost 100), including those implicated in late-onset
Alzheimer’s disease, express proteins that are homologous to beta-amyloid .The
autoantigens in multiple sclerosis, myasthenia gravis, systemic lupus erythromatosus,
Pemphigus Vulgaris and Sjogrens syndrome align with proteins from their respective
reported viral risk factors (and novel suspects), and HIV-1 proteins align with
important components from all compartments of the human immune system. This
even applies to human genetic disorders, as the APP mutations in Alzheimer’s disease
convert the surrounding peptide to sequences that match proteins from commensal
bacteria and from the Norovirus and common cold virus. The mutant proteins in
Huntington’s disease and cystic fibrosis also align with proteins expressed by very
common viruses or phages 8,9. This suggests that a large number of diseases have an
autoimmune component triggered by viral antigens with homology to important
human proteins.
Viruses or phages were long ago proposed as the origin of life 13,17. While
responsible for our existence, they appear to have left behind a legacy of viral derived
human proteins containing short but contiguous and often immunogenic amino acid
stretches homologous to current viral antigens. The autoimmune defence so triggered
may be responsible for a large number of human illnesses. The therapeutic
implications of such mimicry are clearly extensive as it suggests an autoimmune
component in a variety of disorders which might thus benefit from vaccination against
the appropriate pathogen, immunosuppression and pathogen elimination.


Table 1 to 10
Human proteins that match proteins from the translated XMRV genome. The
alignment is shown and accession numbers are provided together with a brief
description of the function of the protein. Unless specifically referenced, these are
copied from the gene descriptions in ENTREZ gene. The matching peptide sequence
in each case is highlighted in bold and contiguous amino acids of 5 or more or longer
stretches of contiguity with few gaps are boxed. The asterisks represent the 5 highest
scoring antigenic amino acids (Table 14) and the grey highlights illustrate contiguous
antigenic stretches that are the most likely B-cell epitopes, and the most likely
candidates for cross-reactivity.
 

VillageLife

Senior Member
Messages
674
Location
United Kingdom
Some things I thought were interesting from the paper,

A homology search comparing retroviral with human proteins revealed short contiguous amino acid strings (typically 5-8 aa) matching human proteins whose dysfunction might be expected to cause fatigue

XMRV proteins are homologous to a variety of human proteins as shown inTable 1-10. Perhaps the most relevant in relation to fatigue are the mitochondrial proteins involved in respiration and oxidative phosphorylation

The XMRV virus expresses predicted proteins with homology to human proteins that are clearly highly relevant to the symptoms encountered in this disease,
including fatigue (mitochondrial respiration), cognitive deficits 49 (glutamate, PI signalling) problems related to olfaction 41(olfactory receptors) muscular pain 41 (acetylcholine receptor and muscle related structural proteins) and the association with many active viral and microbial infections 19 (immune related proteins).

Although these matching strings are short, they are often contiguous and the viral homologues may interfere with their human counterparts in a number of ways. Firstly, many of these stretches are predicted to be antigenic and antibodies to the virus may also target the human homologues.

These homologies, targeted at highly relevant proteins support the implication of the virus in both chronic fatigue syndrome and prostate cancer.

It has recently been shown that Raltegravir potently inhibits XMRV replication and clinical trials in chronic fatigue syndrome and prostate cancer have already been proposed
 

VillageLife

Senior Member
Messages
674
Location
United Kingdom
Because the viral proteins are homologous to human proteins, it is likely that any anybodies generated in response to the virus would target their human homologues. This is supported by the high predicted antigenicity of a number of viral matching proteins and by the presence of autoantibodies to viral matching proteins in chronic fatigue sufferers.
As the human proteins are persistently encountered by the antibody, such an autoimmune response would become selfsustaining, thus no longer requiring the presence of the virus. Indeed, the more successful the immune response against the virus, the greater the risk of autoimmunity, a disastrous pyrrhic victory. This scenario could thus explain the failure to detect the virus in several studies.
:eek::eek::eek:
 

judderwocky

Senior Member
Messages
328
i posted it on my site so there is a hard link if it gets moved

ZOMG it has homologues to Cytochrome and to Glutamate... cytochrome is essential to mitochondrial function and the... krebbs cycle depends on it, and... and glutamate .... isn't glutamate overactivity implicated in a number of psychiatric disorders ( i know studies in germany on OCD peeps with treatment refractory ocd and some studies on pschizophrenia have been done_) this could explain a lot of the weird psychological and neurological effects.... isnt that big in autism????

the more im reading through this study the more i'm astonished.... it makes soo much sense

it looks like there are four homologues to human olfactory receptors????

and GABA???? GABA related
AAB18827.1 gammaaminobutyraldehyde
dehydrogenase

wow.... all of the symptoms....would make soo much sense.

/faint
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
ZOMG it has homologues to Cytochrome and to Glutamate... cytochrome is essential to mitochondrial function and the... krebbs cycle depends on it, and... and glutamate .... isn't glutamate overactivity implicated in a number of psychiatric disorders ( i know studies in germany on OCD peeps with treatment refractory ocd and some studies on pschizophrenia have been done_) this could explain a lot of the weird psychological and neurological effects.... isnt that big in autism????

the more im reading through this study the more i'm astonished.... it makes soo much sense

it looks like there are four homologues to human olfactory receptors????

and GABA???? GABA related
AAB18827.1 gammaaminobutyraldehyde
dehydrogenase

wow.... all of the symptoms....would make soo much sense.

/faint



Interesting thoughts, thanks judderwocky... It makes you think doesn't it!

There's so many possibilities and then they all suddenly come together in a brain-storm and it all suddenly makes so much sense, when you see a bit of research like this!

(I love your 'faint' at the end of your post.)
 

judderwocky

Senior Member
Messages
328
Does anyone know anything about Christopher Carter - other research, academic field, specialty, etc. ?

Ive been looking over the full text version... he throws some interesting ideas out for discussion about autoimmuniyt and bio evolution... but i think there are some holes in them. I think his work on the homologue pairs is very solid, he tosses out some very large and generic discussion pieces... about the origin of life and what not... but the protein homologues are the important bits and that at least will stick even if people don't buy into the viral origin of life question he puts forward or the cuasation for the failed studies (i'm not sure how he thinks someone clears a retroviral infection lol) ... but i think he's just trying to throw ideas up to move the discussion forward. Its already been proven at least in Germany that the "failed" study was unable to find XMRV in the healhty population that new studies have shown is there (in both PC and CFS cohorts). So I think that while he has some interesting connections, the most important really can't be generalized beyond the immediate implications of auto antigens... I think it would also be dangerous to jump to immunusuppresive therapy while we don't know what the viral load... we need follow studies done on these "negative" cohorts to determine phenotype issues well before we assume its simply not present... but the implication of homologue pairs should be investigated


as i see it... he is assuming affinity for immune homologue antigen receptors is going to be the same for the virus and for the human component... they are not identical and their affinity is not going to be the same... i would imagine that it would be some smaller fraction.... but i'm also confused why the paper doesn't address the direct interference that haveing a bunch of look-alike molecules is going to do... im guessing that the viral versions are less functional... and most likely will compete for binding sites with native versions... that alone could explain a host of symptoms... couldn't it? i
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi judderwocky

An interesting thread. I haven't read the original paper yet so I may have more to say later, but I want to talk about viral loads and homology problems.

First, working out the viral load in a CFS patient is going to be very difficult. This virus doesn't exist much in the blood. The evidence is pointing to it being destroyed or inactivated in the blood stream, so it could be very hard to find indeed (although a test that could identify inactivated virus might help). That means it is probably hiding in tissues if the viral load concept has much meaning at all with this virus. The only reliable way to identify viral load would be to grind the patient up in a meat grinder and test the remains - not very useful. I suspect that we could get a close approximation (close enough for treatment purposes anyway) with a lymph node biopsy. My next choice would be to at least try to get an idea from viral load in the throat and lungs. Finally there is a spinal tap, but repeated spinal taps are likely to lead to death or paralysis in many patients, it isn't worth doing over and over during treatment. This is very probably a virus in which we can't measure viral load to objectively determine progress, if we wait for the science to catch up with this problem it could be beyond the lifetime of many of us.

The length of homologous sequences looked at is probably not coincidental. Five to eight amino acids is about the length that antibodies look for. While I suspect some of these proteins might be able to mimic human proteins enough to interfere with cell function, this may not be the case for the most part because protein function depends upon how the protein is folded, and what other charges are on the protein, not just an amino acid sequence. The primary impact is likely to be autoantibodies, but this only explains proteins outside the cell. What is affecting inside the cell? This raises a lot more questions than answers, but that is what attracts scientists is it not? I suspect the answer will lie somewhere else, but a claim that an all out immune assault on XMRV could lead to autoimmune disease or even sudden death would not be impossible. I wonder if this is why some of us occasionally die for no obvious reason? I wonder if this could lead to studies in CFS to determine if we have autoantibodies to these other proteins?

Of course the viral proteins may have evolved to deliberately mimic specific proteins - which they are cannot be determined by simple amino acid sequences. We definitely have to look for specific autoantibodies.

Bye
Alex

I think it would also be dangerous to jump to immunusuppresive therapy while we don't know what the viral load... we need follow studies done on these "negative" cohorts to determine phenotype issues well before we assume its simply not present... but the implication of homologue pairs should be investigated

im guessing that the viral versions are less functional... and most likely will compete for binding sites with native versions... that alone could explain a host of symptoms... couldn't it?
 

jspotila

Senior Member
Messages
1,099
Huh?

I found these comments (in bold) from the Introduction to be troubling:

Chronic fatigue syndrome is an unexplained medical condition characterised
by extreme mental and physical fatigue 25. and by cognitive impairment, depression
and muscular pain and excessive sensitivity to light, sound and smell 41. The condition
has a very high prevalence, for example a figure of 30% of the general population was
recently reported in a study from the Netherlands
46 and there are as many as four
million sufferers in the USA. 7 Perhaps most of the population will experience this
condition at some time in their lives.

I haven't pulled reference 46 but here is the cite: M. van't Leven, et al., "Fatigue and chronic fatigue syndrome-like complaints in the general population," Eur. J. Public Health. 20(3), 251 (2010).

Protein homology means that the proteins were derived from a common ancestor. The paper posits that some XMRV and human proteins are derived from a common ancestor. According to the author, "Viral mimicry of human proteins appears to be a near universal phenomenon. . . . This suggests that a large number of diseases have an autoimmune component triggered by viral antigens with homology to important human proteins." But is "viral mimicry" the same thing as protein homology? And does this reasoning mean that any viral-related illness is an autoimmune disorder? This doesn't make sense to me. HIV/AIDS is not an autoimmune disorder - the immune system cannot fight external pathogens, let alone itself. I don't understand Carter's reasoning.