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Gammaretroviral integration into nucleosomal target DNA in vivo (XMRV)

Jemal

Senior Member
Messages
1,031
J Virol. 2011 May 11. [Epub ahead of print]

Some of the earliest studies of retroviral integration targeting reported that sites of gammaretroviral DNA integration were positively correlated with DNase I hypersensitive sites in chromatin. This led to the suggestion that open chromatin was favorable for integration. More recent deep sequencing experiments confirmed that gammaretroviral integration sites and DNase I cleavage sites are associated in genome-wide surveys. Paradoxically, in vitro studies of integration show that nucleosomal DNA is actually favored over naked DNA, raising the question of whether integration target DNA in chromosomes is wrapped in nucleosomes or nucleosome free. In this study we examined gammaretroviral integration by infecting primary human CD4(+) T lymphocytes with an MLV-based retroviral vector or xenotropic murine leukemia virus-related virus (XMRV), and isolated 32,585 unique integration sites using ligation-mediated PCR and 454 pyrosequencing. CD4+ T lymphocytes were chosen for study because of the particularly dense genome-wide mapping of chromatin features available for comparison. Analysis relative to predicted nucleosome positions showed that gammaretroviruses direct integration into outward-facing major grooves on nucleosome-wrapped DNA, similar to the integration pattern of HIV. Also, a suite of histone modifications correlated with gene activity are positively associated with integration by both MLV and XMRV. Thus we conclude that favored integration near DNase I hypersensitive sites does not imply that integration takes place exclusively in nucleosome free regions.

http://www.ncbi.nlm.nih.gov/pubmed/21561906

Can someone explain this to me, what does it mean? :D
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
http://www.ncbi.nlm.nih.gov/pubmed/21561906

Can someone explain this to me, what does it mean? :D

Good question! :D


What I think I understand, so far, is that they infected human CD4(+) T lymphocytes with XMRV (or an MLV-based retroviral vector), in vivo.
(in vivo = experimentation using a whole, living organism as opposed to a partial or dead organism, so I don't know how they went about this - they can't have infected humans with XMRV.)

Then I think they confirm that they detected XMRV integrated into the human DNA, in a similar pattern to HIV integration. (But I'm not absolutely certain about this!)

If they've demonstrated XMRV integration into human DNA in a living cell, then that's helpful.

That's about all I understand!

I don't know what the implications of their conclusion might be.
 

Cort

Phoenix Rising Founder
Thats' what I got - they showed where in the genome XMRV integrates. Retroviruses integrate themselves into our genome and then use it to replicate. They showed where in our DNA it tends to do that....

It shows the level of interest in XMRV (real virus) that is present, whether or not it is implicated in CFS or prostate cancer. It is a retrovirus that can infect human cells.
 

Jemal

Senior Member
Messages
1,031
Thanks! So does it bring anything new to the table, regaring the contamination controversy?
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Thanks! So does it bring anything new to the table, regaring the contamination controversy?

Another good question! :D

That's what I was wondering...

Is this the first piece of research that has demonstrated XMRV integration into human DNA? There was some evidence of DNA integration in relation to prostate cancer patients, but the validity of that study has now been questioned, due to questions about contamination from the cell line.

If this is the first confirmation since then, then it does show that XMRV can fully infect humans. I think that this is helpful, and another piece of the jigsaw puzzle, but I'm not sure about how significant it is because many scientists already seem to be agreeing that human infection is possible, at least in prostrate cancer patients.

Apart from confirming that full XMRV infection (i.e. DNA integration and therefore viral replication?) is possible in humans (quite helpful!), I don't think that it tells us anything new about the WPI research.

What we need is a demonstration from the WPI or Alter/Lo, that they have found DNA integration in their patients.


So, I'm not certain about the significance of this study in relation to XMRV generally.
The evidence and knowledge does seem to be building up slowly but surely.
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
I probably have this wrong, but didn't Alter/Lo find XMRV intergrated into human DNA in one end/side. At one conference Coffin was pressing Alter to find XMRV fully intergrated into human DNA as in both side/ends???
 

Otis

Señor Mumbler
Messages
1,117
Location
USA
I probably have this wrong, but didn't Alter/Lo find XMRV intergrated into human DNA in one end/side. At one conference Coffin was pressing Alter to find XMRV fully intergrated into human DNA as in both side/ends???

I'm pretty fuzzy these days but I'm pretty sure Silverman showed XMRV was integrated into DNA in one end and that Coffin's challenge to Lo/Alter was to isolate and fully sequence the PLMVs they found.
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
I'm pretty fuzzy these days but I'm pretty sure Silverman showed XMRV was integrated into DNA in one end and that Coffin's challenge to Lo/Alter was to isolate and fully sequence the PLMVs they found.

Sounds right and makes sense to me as the fuzz has been pretty thick on me as well. Thanks
 

Daffodil

Senior Member
Messages
5,873
i was told this paper would prove that XMRV is a real human pathogen that integrates into the genome and not a contaminant. i dont know if integration sites have been shown before.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
i was told this paper would prove that XMRV is a real human pathogen that integrates into the genome and not a contaminant. i dont know if integration sites have been shown before.

That's good to hear, but that still doesn't prove that what the WPI have detected is not a contaminant.
Unfortunately the questions of contamination in relation to the WPI will probably still remain.
But it does add another piece to the jigsaw puzzle of knowledge about XMRV.
I've only read the abstract though, so I don't know if there is more significant information in the full text.
 

ixchelkali

Senior Member
Messages
1,107
Location
Long Beach, CA
gammaretroviruses direct integration into outward-facing major grooves on nucleosome-wrapped DNA
You know, not a day goes by without my saying that. ;)

So now we know how and where XMRV and related gammaretroviruses integrate. We just don't know whether we should care. :D

Seriously, it's good to see that research is proceeding. I wonder how this integration compares with that of other gammaretroviruses, like Feline Leukemia Virus?
 

currer

Senior Member
Messages
1,409
Maybe this study would help future researchers to know where to look for integration into human DNA, if they can show a preference for certain integration sites in this paper?
 

Enid

Senior Member
Messages
3,309
Location
UK
It is good to see how this research is moving along now. A real mine of information on the latest here - thanks to you all.