How XMRV arose a mechanism

[Gerwyn]

A new kind of immune response has been discovered which is specific to retroviruses.it uses the genes of endogenous retroviruses and the proteins they make to inhibit retroviruses which are closely related. There are two main ways that they do this.

The first is they alter the cell receptors so that no more virus can get in

The second way is that they partly substitute their proteins for the ones belonging to the invader in the invader's envelope

So a mouse Exogenous gammaretrovirus could be changed into another gammaretrovirus which could no longer infect mouse cells but be different enough to be able to bind to cellular entry receptors in another host and be dissimilar enough to resist the intrisic immune system in humans and so jump species. and so XMRV may be born and ultimately that process may reverse itself

If anyone wants anymore info on this thread please let me know The following has more detail but this defence is a bit like viral Judo!

ature Immunology 5, 1109 - 1115 (2004)
Published online: 20 October 2004; | doi:10.1038/ni1125
Intrinsic immunity: a front-line defense against viral attack

Paul D Bieniasz


In addition to the conventional innate and acquired immune responses, complex organisms have evolved an array of dominant, constitutively expressed genes that suppress or prevent viral infections. Two major cellular defenses against infection by retroviruses are the Fv1 and TRIM5 class of inhibitors that target incoming retroviral capsids and the APOBEC3 class of cytidine deaminases that hypermutate and destabilize retroviral genomes. Additional, less well characterized activities also inhibit viral replication. Here, the present understanding of these 'intrinsic' immune mechanisms is reviewed and their role in protection from retroviral infection is discussed.

The simplest forms of what could be called intrinsic immunity are special cases of viral interference, which arise because retroviral genomes are inherited like cellular genes when they infect germline cells. The ability to express 'endogenous' viral proteins in either intact or defective forms can sometimes induce resistance to infection by related exogenous retroviruses. A classical example of interference among exogenous retroviruses occurs when cellular receptors become blocked and/or downregulated as a consequence of retroviral infection and expression of viral envelope proteins1, 2. Therefore, when an organism carries an endogenous retrovirus, its cells can, in effect, synthesize their own exquisitely specific and effective viral entry inhibitor and become resistant to infection by other retroviruses that use the blocked receptor. Although no examples of such a phenomenon are

 

[Mark]

Thanks for this Gerwyn. It sounds to me that this behaviour completes the circle of a subject we discussed some months ago - the lifecycle of endogenous and exogenous retroviruses - and it appears to confirm our speculation about all that. The behaviour described seems to be an explicit mechanism supporting a theory I put forward at the time, so I'm going to try to describe that lifecycle in layman's terms. Hopefully helpful to the non-scientists, and the scientists can tell me whether I've got it right...

So: retrovirus infects an individual of some species. The DNA sequence of the retrovirus is not found in the individual's DNA, meaning that this retrovirus is exogenous to that species. The retrovirus infects certain cells within that individual, using its reverse transcriptase enzyme to write its RNA sequence into part of the DNA of the cells it infects.

If the retrovirus infects cells that are involved in reproduction, it is then possible for the retroviral DNA sequence to be passed on to descendants of that individual. If this happens, the retrovirus DNA will then be encoded into the DNA of the individual. Eventually, over many generations, any successful retrovirus will thus 'succeed' in getting its DNA encoded into the species as a whole - at which point the retrovirus is then endogenous to the species.

Due to this process, our DNA contains a huge 'database' of old retroviruses that have infected the species and become absorbed into the DNA in this way - effectively a library of ancient retroviruses. Some scientists believe that this process of absorption of retroviruses into the species DNA may be a fundamentally important mechanism that drives the evolution of a species. The existence of the 'library' was only recently discovered, and thus much of the DNA previously considered to be 'junk' is actually a sort of historical archive.

What role this archive may or may not play is almost pure speculation at this point, but there are some fairly obvious and intriguing possibilities. The most obvious thought - to a computer programmer at least - is that the body may be able to somehow call on the information in this database of retroviruses in order to fight new infections. As a computer guy myself, fascinated by the highly suggestive parallels between the way biological DNA/RNA works and the way computer systems work, this library of retroviruses immediately looks to me rather like a 'quarantine area' for viruses, and it seems inconceivable that the body would not make use of this information somehow. (A good rule of thumb for scientists here, IMO, would be something along the lines of Murphy's Law: If you can imagine it, and it makes sense, and it's technically feasible, and would be evolutionarily beneficial, then it almost certainly happens).

So finally we come to the study Gerwyn referenced, which seems to present tentative evidence of a mechanism that does exactly this, and also completes the circle of the retroviral lifecycle. What the body is able to do is exploit the property of retroviruses that, after they infect a cell, they shut down the receptors on that cell and thus prevent it being infected again. (This is the part I'm not sure I understand, but I'm interpreting that the retrovirus is preventing a second retrovirus identical to itself from wasting its time infecting this cell because it's already infected - go find another one to infect, brother! - I saw this mechanism discussed very recently in another research paper on ordinary viruses, showing that their 'communication' with each other enables them to spread more efficiently. Or maybe the retrovirus also gains from preventing the cell from being infected by a different retrovirus?).

So: what the body can do, when faced with a new, unknown retrovirus, is to search through its library of endogenous retroviruses for something with a similar sequence to the unknown invader. When it finds some similar retroviruses, it causes those retroviruses to start producing the viral proteins which do the job of blocking the relevant receptors in the body's cells. If the new retrovirus is similar enough to the endogenous ones, this will succeed in preventing - or at least inhibiting - the new retrovirus from spreading and infecting cells in the body.

The second part of this defensive strategy is that the viral proteins the body produces from the endogenous retrovirus can then substitute themselves into the new retrovirus's envelope, which would effectively create a brand new species of retrovirus: a mixture of the invader and the sequences from the endogenous retroviral proteins created by the body. The newly created retrovirus should be harmless to the host, because it contains these endogenous sequences which the host species has evolved to be able to survive - the host has turned the invading retrovirus into something it can deal with.

However, the newly created retrovirus is now a brand new species of retrovirus, which is in theory capable of infecting a different species. And so, a new retrovirus is born, ready to be transmitted to a new species as an exogenous retrovirus.

I hope I've described the above correctly - please correct anything where I've used the wrong terminology etc or just misunderstood the mechanism. This whole area is absolutely fascinating to me, particularly because the parallels with how computer operating systems work is so compelling. As soon as I read a bit about endogenous and exogenous retroviruses, it immediately struck me that some mechanism such as that described in the study Gerwyn found must take place. It's just inconceivable to me that nature would not make use of this sort of information in some way, and understanding this evolutionary dynamic seems to be fundamental to understanding what retroviruses are, so it's very exciting to see some definitive confirmation of that mechanism. Thanks again Gerwyn!

Oh - one final thought: I wonder what might be the relationship between this process and the result observed by the 2nd UK XMRV study? If I have it right: they found, in 4% of controls, that it looked like they had found XMRV, but on closer inspection they concluded they were probably actually detecting lots of very similar endogenous retroviruses, not XMRV. Isn't that exactly what one would expect to see in a host that was successfully fighting off XMRV infection using the mechanism described above? If that were true, then the specific endogenous retroviruses they detected might be part of the body's successful defence against XMRV - in which case comparing the 'code' might enable you to work out how these activated endogenous retroviruses might be helping...and even suggest a possible line of treatment for people who perhaps lack the relevant endogenous retroviruses to fight off XMRV - infect them with those? Swallow a spider to catch a fly?...

 

[Gerwyn]

Thanks for this Gerwyn. It sounds to me that this behaviour completes the circle of a subject we discussed some months ago - the lifecycle of endogenous and exogenous retroviruses - and it appears to confirm our speculation about all that. The behaviour described seems to be an explicit mechanism supporting a theory I put forward at the time, so I'm going to try to describe that lifecycle in layman's terms. Hopefully helpful to the non-scientists, and the scientists can tell me whether I've got it right...

So: retrovirus infects an individual of some species. The DNA sequence of the retrovirus is not found in the individual's DNA, meaning that this retrovirus is exogenous to that species. The retrovirus infects certain cells within that individual, using its reverse transcriptase enzyme to write its RNA sequence into part of the DNA of the cells it infects.

If the retrovirus infects cells that are involved in reproduction, it is then possible for the retroviral DNA sequence to be passed on to descendants of that individual. If this happens, the retrovirus DNA will then be encoded into the DNA of the individual. Eventually, over many generations, any successful retrovirus will thus 'succeed' in getting its DNA encoded into the species as a whole - at which point the retrovirus is then endogenous to the species.

Due to this process, our DNA contains a huge 'database' of old retroviruses that have infected the species and become absorbed into the DNA in this way - effectively a library of ancient retroviruses. Some scientists believe that this process of absorption of retroviruses into the species DNA may be a fundamentally important mechanism that drives the evolution of a species. The existence of the 'library' was only recently discovered, and thus much of the DNA previously considered to be 'junk' is actually a sort of historical archive.

What role this archive may or may not play is almost pure speculation at this point, but there are some fairly obvious and intriguing possibilities. The most obvious thought - to a computer programmer at least - is that the body may be able to somehow call on the information in this database of retroviruses in order to fight new infections. As a computer guy myself, fascinated by the highly suggestive parallels between the way biological DNA/RNA works and the way computer systems work, this library of retroviruses immediately looks to me rather like a 'quarantine area' for viruses, and it seems inconceivable that the body would not make use of this information somehow. (A good rule of thumb for scientists here, IMO, would be something along the lines of Murphy's Law: If you can imagine it, and it makes sense, and it's technically feasible, and would be evolutionarily beneficial, then it almost certainly happens).

So finally we come to the study Gerwyn referenced, which seems to present tentative evidence of a mechanism that does exactly this, and also completes the circle of the retroviral lifecycle. What the body is able to do is exploit the property of retroviruses that, after they infect a cell, they shut down the receptors on that cell and thus prevent it being infected again. (This is the part I'm not sure I understand, but I'm interpreting that the retrovirus is preventing a second retrovirus identical to itself from wasting its time infecting this cell because it's already infected - go find another one to infect, brother! - I saw this mechanism discussed very recently in another research paper on ordinary viruses, showing that their 'communication' with each other enables them to spread more efficiently. Or maybe the retrovirus also gains from preventing the cell from being infected by a different retrovirus?).

So: what the body can do, when faced with a new, unknown retrovirus, is to search through its library of endogenous retroviruses for something with a similar sequence to the unknown invader. When it finds some similar retroviruses, it causes those retroviruses to start producing the viral proteins which do the job of blocking the relevant receptors in the body's cells. If the new retrovirus is similar enough to the endogenous ones, this will succeed in preventing - or at least inhibiting - the new retrovirus from spreading and infecting cells in the body.

The second part of this defensive strategy is that the viral proteins the body produces from the endogenous retrovirus can then substitute themselves into the new retrovirus's envelope, which would effectively create a brand new species of retrovirus: a mixture of the invader and the sequences from the endogenous retroviral proteins created by the body. The newly created retrovirus should be harmless to the host, because it contains these endogenous sequences which the host species has evolved to be able to survive - the host has turned the invading retrovirus into something it can deal with.

However, the newly created retrovirus is now a brand new species of retrovirus, which is in theory capable of infecting a different species. And so, a new retrovirus is born, ready to be transmitted to a new species as an exogenous retrovirus.

I hope I've described the above correctly - please correct anything where I've used the wrong terminology etc or just misunderstood the mechanism. This whole area is absolutely fascinating to me, particularly because the parallels with how computer operating systems work is so compelling. As soon as I read a bit about endogenous and exogenous retroviruses, it immediately struck me that some mechanism such as that described in the study Gerwyn found must take place. It's just inconceivable to me that nature would not make use of this sort of information in some way, and understanding this evolutionary dynamic seems to be fundamental to understanding what retroviruses are, so it's very exciting to see some definitive confirmation of that mechanism. Thanks again Gerwyn!

Oh - one final thought: I wonder what might be the relationship between this process and the result observed by the 2nd UK XMRV study? If I have it right: they found, in 4% of controls, that it looked like they had found XMRV, but on closer inspection they concluded they were probably actually detecting lots of very similar endogenous retroviruses, not XMRV. Isn't that exactly what one would expect to see in a host that was successfully fighting off XMRV infection using the mechanism described above? If that were true, then the specific endogenous retroviruses they detected might be part of the body's successful defence against XMRV - in which case comparing the 'code' might enable you to work out how these activated endogenous retroviruses might be helping...and even suggest a possible line of treatment for people who perhaps lack the relevant endogenous retroviruses to fight off XMRV - infect them with those? Swallow a spider to catch a fly?...

pretty much spot on the mechanisim is called the intrisic immune system.We have innate aquired and intrinsic

 

[Gerwyn]

Thanks for this Gerwyn. It sounds to me that this behaviour completes the circle of a subject we discussed some months ago - the lifecycle of endogenous and exogenous retroviruses - and it appears to confirm our speculation about all that. The behaviour described seems to be an explicit mechanism supporting a theory I put forward at the time, so I'm going to try to describe that lifecycle in layman's terms. Hopefully helpful to the non-scientists, and the scientists can tell me whether I've got it right...

So: retrovirus infects an individual of some species. The DNA sequence of the retrovirus is not found in the individual's DNA, meaning that this retrovirus is exogenous to that species. The retrovirus infects certain cells within that individual, using its reverse transcriptase enzyme to write its RNA sequence into part of the DNA of the cells it infects.

If the retrovirus infects cells that are involved in reproduction, it is then possible for the retroviral DNA sequence to be passed on to descendants of that individual. If this happens, the retrovirus DNA will then be encoded into the DNA of the individual. Eventually, over many generations, any successful retrovirus will thus 'succeed' in getting its DNA encoded into the species as a whole - at which point the retrovirus is then endogenous to the species.

Due to this process, our DNA contains a huge 'database' of old retroviruses that have infected the species and become absorbed into the DNA in this way - effectively a library of ancient retroviruses. Some scientists believe that this process of absorption of retroviruses into the species DNA may be a fundamentally important mechanism that drives the evolution of a species. The existence of the 'library' was only recently discovered, and thus much of the DNA previously considered to be 'junk' is actually a sort of historical archive.

What role this archive may or may not play is almost pure speculation at this point, but there are some fairly obvious and intriguing possibilities. The most obvious thought - to a computer programmer at least - is that the body may be able to somehow call on the information in this database of retroviruses in order to fight new infections. As a computer guy myself, fascinated by the highly suggestive parallels between the way biological DNA/RNA works and the way computer systems work, this library of retroviruses immediately looks to me rather like a 'quarantine area' for viruses, and it seems inconceivable that the body would not make use of this information somehow. (A good rule of thumb for scientists here, IMO, would be something along the lines of Murphy's Law: If you can imagine it, and it makes sense, and it's technically feasible, and would be evolutionarily beneficial, then it almost certainly happens).

So finally we come to the study Gerwyn referenced, which seems to present tentative evidence of a mechanism that does exactly this, and also completes the circle of the retroviral lifecycle. What the body is able to do is exploit the property of retroviruses that, after they infect a cell, they shut down the receptors on that cell and thus prevent it being infected again. (This is the part I'm not sure I understand, but I'm interpreting that the retrovirus is preventing a second retrovirus identical to itself from wasting its time infecting this cell because it's already infected - go find another one to infect, brother! - I saw this mechanism discussed very recently in another research paper on ordinary viruses, showing that their 'communication' with each other enables them to spread more efficiently. Or maybe the retrovirus also gains from preventing the cell from being infected by a different retrovirus?).

So: what the body can do, when faced with a new, unknown retrovirus, is to search through its library of endogenous retroviruses for something with a similar sequence to the unknown invader. When it finds some similar retroviruses, it causes those retroviruses to start producing the viral proteins which do the job of blocking the relevant receptors in the body's cells. If the new retrovirus is similar enough to the endogenous ones, this will succeed in preventing - or at least inhibiting - the new retrovirus from spreading and infecting cells in the body.

The second part of this defensive strategy is that the viral proteins the body produces from the endogenous retrovirus can then substitute themselves into the new retrovirus's envelope, which would effectively create a brand new species of retrovirus: a mixture of the invader and the sequences from the endogenous retroviral proteins created by the body. The newly created retrovirus should be harmless to the host, because it contains these endogenous sequences which the host species has evolved to be able to survive - the host has turned the invading retrovirus into something it can deal with.

However, the newly created retrovirus is now a brand new species of retrovirus, which is in theory capable of infecting a different species. And so, a new retrovirus is born, ready to be transmitted to a new species as an exogenous retrovirus.

I hope I've described the above correctly - please correct anything where I've used the wrong terminology etc or just misunderstood the mechanism. This whole area is absolutely fascinating to me, particularly because the parallels with how computer operating systems work is so compelling. As soon as I read a bit about endogenous and exogenous retroviruses, it immediately struck me that some mechanism such as that described in the study Gerwyn found must take place. It's just inconceivable to me that nature would not make use of this sort of information in some way, and understanding this evolutionary dynamic seems to be fundamental to understanding what retroviruses are, so it's very exciting to see some definitive confirmation of that mechanism. Thanks again Gerwyn!

Oh - one final thought: I wonder what might be the relationship between this process and the result observed by the 2nd UK XMRV study? If I have it right: they found, in 4% of controls, that it looked like they had found XMRV, but on closer inspection they concluded they were probably actually detecting lots of very similar endogenous retroviruses, not XMRV. Isn't that exactly what one would expect to see in a host that was successfully fighting off XMRV infection using the mechanism described above? If that were true, then the specific endogenous retroviruses they detected might be part of the body's successful defence against XMRV - in which case comparing the 'code' might enable you to work out how these activated endogenous retroviruses might be helping...and even suggest a possible line of treatment for people who perhaps lack the relevant endogenous retroviruses to fight off XMRV - infect them with those? Swallow a spider to catch a fly?...

pretty much spot on the mechanisim is called the intrisic immune system.We have innate aquired and intrinsic

 

[natasa778]

Some scientists believe that this process of absorption of retroviruses into the species DNA may be a fundamentally important mechanism that drives the evolution of a species.

Yes, speculated to have influenced development of intelligence in humans.

This is a nice review:

Endogenous retroviruses in systemic response to stress signals.
Infection of germline cells with retroviruses initiates permanent proviral colonization of the germline genome. The germline-integrated proviruses, called endogenous retroviruses (ERVs), are inherited to offspring in a Mendelian order and belong to the transposable element family. Endogenous retroviruses and other long terminal repeat retroelements constitute ~8% and ~10% of the human and mouse genomes, respectively. It is likely that each individual has a distinct genomic ERV profile. Recent studies have revealed that a substantial fraction of ERVs retains the coding potentials necessary for virion assembly and replication. There are several layers of potential mechanisms controlling ERV expression: intracellular transcription environment (e.g., transcription factor pool, splicing machinery, hormones), epigenetic status of the genome (e.g., proviral methylation, histone acetylation), profile of transcription regulatory elements on each ERV's promoter, and a range of stress signals (e.g., injury, infection, environment). Endogenous retroviruses may exert pathophysiologic effects by infection followed by random reintegration into the genome, by their gene products (e.g., envelope, superantigen), and by altering the expression of neighboring genes. Several studies have provided evidence that ERVs are associated with a range of pathogenic processes involving multiple sclerosis, systemic lupus erythematosus, breast cancer, and the response to burn injury. For instance, the proinflammatory properties of the human ERV-W envelope protein play a central role in demyelination of oligodendrocytes. As reviewed in this article, recent advances in ERV biology and mammalian genomics suggest that ERVs may have a profound influence on various pathogenic processes including the response to injury and infection. Understanding the roles of ERVs in the pathogenesis of injury and infection will broaden insights into the underlying mechanisms of systemic immune disorder and organ failure in these patients. PMID: 18317406 Shock. 2008 Aug;30(2):105-16. Cho K, Lee YK, Greenhalgh DG. Burn Research, Shriners Hospitals for Children, and Department of Surgery, University of California Davis, Sacramento, CA 95817, USA. kcho@ucdavis.edu

 

[natasa778]

What the body is able to do is exploit the property of retroviruses that, after they infect a cell, they shut down the receptors on that cell and thus prevent it being infected again. (This is the part I'm not sure I understand, but I'm interpreting that the retrovirus is preventing a second retrovirus identical to itself from wasting its time infecting this cell because it's already infected - go find another one to infect, brother! - I saw this mechanism discussed very recently in another research paper on ordinary viruses, showing that their 'communication' with each other enables them to spread more efficiently. Or maybe the retrovirus also gains from preventing the cell from being infected by a different retrovirus?).

this is called Superinfection Exclusion, was discussed on another thread recently

 

[natasa778]

So: what the body can do, when faced with a new, unknown retrovirus, is to search through its library of endogenous retroviruses for something with a similar sequence to the unknown invader. When it finds some similar retroviruses, it causes those retroviruses to start producing the viral proteins which do the job of blocking the relevant receptors in the body's cells.

Meaning that endogenous retroviral elements in each individual would, at least partially, determine host susceptibility to particular infection. ?

Interesting that genetic polymorphisms (influenced/created by endogenous retroviral elements??) in relevant membrane receptors determine susceptibility to HIV and speed of progression to AIDS. In addition to that those chemokine receptor polymorphisms influence vulnerability to, and the degree of neurological impairment/autism symptoms in HIV positive (even in absence of AIDS).

Gerwyn, have you seen the recent study showing xmrv integration by chemokine receptor introns, do you think it would be relevant here?

 

[Gerwyn]

Meaning that endogenous retroviral elements in each individual would, at least partially, determine host susceptibility to particular infection. ?

Interesting that genetic polymorphisms (influenced/created by endogenous retroviral elements??) in relevant membrane receptors determine susceptibility to HIV and speed of progression to AIDS. In addition to that those chemokine receptor polymorphisms influence vulnerability to, and the degree of neurological impairment/autism symptoms in HIV positive (even in absence of AIDS).

Gerwyn, have you seen the recent study showing xmrv integration by chemokine receptor introns, do you think it would be relevant here?

Absolutely If you can send a copy link that will overcome my technological ineptitude i would be grateful that is the sort of thing I,m specifically looking for

 

[Gerwyn]

this is called Superinfection Exclusion, was discussed on another thread recently

yes exactly but retro specific

 

[natasa778]

Sorry blunder, not xmrv but 'only' murine leukemia virus

http://informahealthcare.com/doi/abs/10.3109/08923970902862284 if you have access to full paper, abstract below

Viral sequence integration into introns of chemokine receptor genes.

Viral DNA sequences are able to integrate into the non-coding DNA sections of the genome of human cells which have been infected, either spontaneously or experimentally. We have made a data-base search for integration events of non-endogenous viruses into the introns of chemokine receptor sequences. A BLAST search of all viral DNA sequences, using the intronic sequences as "Query," returned several significant alignments. However, due to the high reiteration rate of the non-coding sequences in the human genome, it became necessary to re-examine the individual alignments to verify whether the virus-flanking intronic sequence was really located in a chemokine receptor intron. We found only one unquestionable event of viral insertion of a section of a long terminal repeat of the murine leukemia virus within the first intron of the CC chemokine receptor 7 gene. Possible biological effects of such an insertion are discussed. Further experimental or clinical research could demonstrate the occurrence of other intronic viral insertions in human chemokine receptor genes. PMID: 19874227 Immunopharmacol Immunotoxicol. 2009;31(4):589-94. Panaro MA, et al, Department of Human Anatomy and Histology, University of Bari, Bari, Italy. ma.panaro@anatomia.uniba.it

 

[natasa778]

More on xmrv integration:

http://www.pnas.org/content/104/5/1655.full
...Three provirus integration sites in DNA isolated directly from primary prostate tissues are reported in this study: CREB5, NFATc3, and APPBP2. CREB5, a member of the CRE (cAMP response element)-binding protein family, specifically binds to CRE as a homodimer or a heterodimer with c-Jun or CRE-BP1 and functions as a CRE-dependent transactivator (21, 22). NFATc3 is a member of the nuclear factors of activated T cells DNA-binding transcription complex and plays a role in the regulation of gene expression in T cells and immature thymocytes (2327). Interestingly, NFATc3 is a site of integration of the SL3-3 murine lymphomagenic retrovirus in mice in which integration represses NFATc3 expression in lymphomas (40). NFATc3-deficient mice infected with SL3-3 virus develop T cell lymphomas with increased frequencies compared with wild-type mice. APPBP2 has homology to the molecular motor protein, kinesin light chain, involved in transport of proteins along microtubules (30). APPBP2, which also binds microtubules, is expressed in a wide range of cell types and functions in the trafficking of amyloid precursor protein (30, 41). Remarkably, APPBP2 also interacts with the androgen receptor and suppresses androgen signaling (31, 32). At present we do not know whether these XMRV integration events affect gene expression and function of these factors or whether the integrations have direct or indirect effects on the etiology or progression of prostate cancer. However, our findings of integration sites for XMRV in human prostate DNA validate that bona fide, naturally occurring XMRV infections of humans have occurred among a subset of prostate cancer cases

I'm esp. fascinated by CREB not sure about CREB5 in particular http://www.ihop-net.org/UniPub/iHOP/gs/94782.html, but CREB function in general is crucial in brain function / neuronal gene expression, esp. early in development, and also heavily involved in various aspects of immunity s)ee bottom half of page http://tinyurl.com/ydnq34f)

CREB (cAMP response element-binding) proteins are transcription factors which bind to cAMP response elements in DNA and thereby increase or decrease the transcription of certain genes. CREB has been widely studied due to its role in diverse functions such as circadian rhythms, drug addiction and inflammatory pathways. Both CREB and several transcriptional regulators have been linked to epigenetic factors involved in cognitive and behavioural developmental disorders [15721740]. CREB deficient mice for example were shown to exibit less active and exploratory behaviours in novel environments, as well as memory deficits in spatial learning and fear conditioning http://tinyurl.com/yc85wah

 

[Gerwyn]

More on xmrv integration:



I'm esp. fascinated by CREB – not sure about CREB5 in particular http://www.ihop-net.org/UniPub/iHOP/gs/94782.html, but CREB function in general is crucial in brain function / neuronal gene expression, esp. early in development, and also heavily involved in various aspects of immunity s)ee bottom half of page http://tinyurl.com/ydnq34f)

wow Thanks Natasa 778(do you mind being called Natasa without the 778 because i almost missed that out now) Ok gene manipulation in T cells really worth persuing .Do we know any more about the nature of the genes involved OR havei just missed it in the above.I will have a really close look later for a possible nitric oxide synthase link---my pet theory at the moment!

 

[natasa778]

Gerwyin you won't believe this but CREB and NOS are closely interlinked and influence each other.

As in:
Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26997/?tool=pubmed


And then the other way around:
A Nitric Oxide Signaling Pathway Controls CREB-Mediated Gene Expression in Neurons http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26997/?tool=pubmed


(somehow whenever calcium signalling is involved, esp. through voltage gated channels, things always work in both directions!)

this is what I've got on CREB in immunity/inflammation through that link:

Of special interest should be several recent observation of reduced responsiveness to stimulation of both B and T lympocytes following elevations of cytosolic free calcium [12805281] (see Infectios_Agents). Although LTCC are mainly expressed in excitable cells, recent evidence points to the involvement of voltage-insensitive dihydropyridine channels in calcium pathways of both B and T lymphocytes [8631746, 9550376, 14981074]. Calcium influx through the plasma membrane of lymphocytes is essential for their activation, proliferation, cytokine secretion and apoptosis [16766050]. Calcium and CREB-mediated upregulation of chemokine receptors mRNA has been observed in T lympocytes, whereby activation of CXCR4 by viral proteins leads to increased viral infectivity [11874984, 14563373].

Furthermore, differences in calcium mobilization are associated with differentiation of naive CD4+ T cells into Th1 and Th2 subsets. Because LTCC are induced during Th2 but not Th1 cell differentiation, it has been suggested that LTCC blockers may be useful in the treatments of Th2-mediated pathologies. One such agent, nicardipine, was able to inhibit the Th2-mediated autoimmune glomerulonephritis induced by injecting Brown Norway (BN) rats with heavy metals, but had no effect on Th1-mediated experimental encephalomyelitis [15100258, 15777162, 14708347, 12721099].

also further down on a slightly different note but probably relevant to CFS:

Relative to autism it may be of interest to mention that a specific mechanism has recently been suggested, whereas the crosstalk between chemokine receptors and neuropeptide membrane receptors serves as a bridge between the immune and nervous systems. Chemokine receptors, a family of G protein-coupled receptors, are widely expressed by cells of immune and nervous systems, including neurons. The activation of several other receptors, such as opioid, vasoactive intestinal peptide, or adenosine receptors, often has inhibitory effects on chemokine receptors by a mechanism termed heterologous desensitization, resulting in suppression of immune responses. Conversely, activation of chemokine receptors also induces desensitization of mu-opioid receptors (see Infectious_Agents and Related_Receptors). In addition to that, prior exposure of neuronal cells to chemokine treatment enhances the sensitivity of transient receptor potential vanilloid 1 (TRPV1) calcium channel, which is critical for sensing of pain [16204635] (see Sensory/Motor).

yes Natasa is fine, 778 sort of a retroelement from another forum ☺

 

[Gerwyn]

Gerwyin you won't believe this but CREB and NOS are closely interlinked and influence each other.

As in:
Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26997/?tool=pubmed


And then the other way around:
A Nitric Oxide Signaling Pathway Controls CREB-Mediated Gene Expression in Neurons http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26997/?tool=pubmed


(somehow whenever calcium signalling is involved, esp. through voltage gated channels, things always work in both directions!)

this is what I've got on CREB in immunity/inflammation through that link:


also further down on a slightly different note but probably relevant to CFS:



yes Natasa is fine, 778 sort of a retroelement from another forum ☺

you are quite brilliant! high NO will deplete glutathione tgif and a whole host of our measured abnormalities if there is gene feedback this would explain even more know anything about the relationship with the beta interreron gene?

 

[Gerwyn]

creb mediated upregulation could well cut it!

 

[natasa778]

An ATF/CREB binding site is required for virus induction of the human interferon beta gene
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC48614/

also this one http://mcb.asm.org/cgi/content/abstract/20/17/6342

 

[natasa778]

Martin L. Pall website

http://thetenthparadigm.org/ lots on NO pathways in CFS etc

 

[Gerwyn]

An ATF/CREB binding site is required for virus induction of the human interferon beta gene
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC48614/

also this one http://mcb.asm.org/cgi/content/abstract/20/17/6342

All i can say to that is bingo! really superb researching

 

[natasa778]

Thanks Gerwyn. Please do post if you figure out more in this area as could relate to XMRV specifically

 

[Gerwyn]

Thanks Gerwyn. Please do post if you figure out more in this area as could relate to XMRV specifically

i will a soon asi can put a condensed coherent proposition linking everything together As best I can! thanks again natasa-You have saved me hours!