latent HHV6A integrates in telomeres of human chromosomes in vivo and in vitro

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kelly posted this to co-cure today

[if: I'd love it if one of our local science geniuses could explain any potential relevance of this for ME/CFS.]

Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5563-8. Epub 2010 Mar 8.
The latent human herpesvirus-6A genome specifically integrates in telomeres
of human chromosomes in vivo and in vitro.

Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, Lund
TC, Tolar J, De Meirleir K, Montoya JG, Komaroff AL, Ambros PF, Medveczky
PG.

Department of Molecular Medicine, University of South Florida College of
Medicine, Tampa, FL 33612.

Previous research has suggested that human herpesvirus-6 (HHV-6) may
integrate into host cell chromosomes and be vertically transmitted in the
germ line, but the evidence-primarily fluorescence in situ hybridization
(FISH)-is indirect.

We sought, first, to definitively test these two hypotheses. Peripheral
blood mononuclear cells (PBMCs) were isolated from families in which several
members, including at least one parent and child, had unusually high copy
numbers of HHV-6 DNA per milliliter of blood. FISH confirmed that HHV-6 DNA
colocalized with telomeric regions of one allele on chromosomes 17p13.3,
18q23, and 22q13.3, and that the integration site was identical among
members of the same family. Integration of the HHV-6 genome into TTAGGG
telomere repeats was confirmed by additional methods and sequencing of the
integration site. Partial sequencing of the viral genome identified the same
integrated HHV-6A strain within members of families, confirming vertical
transmission of the viral genome.

We next asked whether HHV-6A infection of nave cell lines could lead to
integration. Following infection of nave Jjhan and HEK-293 cell lines by
HHV-6, the virus integrated into telomeres. Reactivation of integrated
HHV-6A virus from individuals' PBMCs as well as cell lines was successfully
accomplished by compounds known to induce latent herpesvirus replication.

Finally, no circular episomal forms were detected even by PCR. Taken
together, the data suggest that HHV-6 is unique among human herpesviruses:
it specifically and efficiently integrates into telomeres of chromosomes
during latency rather than forming episomes, and the integrated viral genome
is capable of producing virions.


PMID: 20212114 [PubMed - in process]

-
 

Gemini

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islandfinn,

Thanks for posting this important HHV-6 research development.

A bit of history, Dr. Ablashi, a co-author of this paper, co-discovered HHV-6 while working in Robert Gallo's lab at NIH in 1986. Between 1988-1998 he and other researchers published results from 17 CFS studies representing a total of 1473 patients finding on average 64% HHV-6A positive.

Herpes antiviral drugs (acyclovir and its derivatives) have been tried against HHV-6. Maybe there are patients on the forum with treatment experiences they could share?

HHV-6 can infect B-cells {Science: 234: 596-601, 1986}, T-cells {Nature: 329: 207,1987}, NK cells {Nature: 362: 458-62, 1993} and monocytes & macrophages { J of Gen Virology: 72: 1401-08, 1991}.

An interesting question: how many XMRV+ are also HHV-6A+ and what might that mean?

Gemini
 

Dr. Yes

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Hi IF,

This was posted on another thread a little while back with some discussion.. I can't remember where, but if I can find it I'll post the link here (just letting everyone know so THEY might be able to find it!)

It really is a major discovery, and I'm surprised I haven't heard more about it since then.
 

wciarci

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From what I have read, they are also studying HHV 6 chromosome intertwined with bi-polar. In my family if you don't have bi-polar, your have CFS, FM or another autoimmune disease. I can count 10 close relatives with bipolar and the same number with auto-immune. Studies have shown that bi-polar is the result of dysfunctional mitochondria. (Japan and Harvard). I have also been reading about the role of calcium and iron in dysfunctional mitochondria. It appears that some forms of MS have irregular iron mechanisms.

Wendy
 

Hope123

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islandfinn,

Thanks for posting this important HHV-6 research development.

A bit of history, Dr. Ablashi, a co-author of this paper, co-discovered HHV-6 while working in Robert Gallo's lab at NIH in 1986. Between 1988-1998 he and other researchers published results from 17 CFS studies representing a total of 1473 patients finding on average 64% HHV-6A positive.

Herpes antiviral drugs (acyclovir and its derivatives) have been tried against HHV-6. Maybe there are patients on the forum with treatment experiences they could share?

HHV-6 can infect B-cells {Science: 234: 596-601, 1986}, T-cells {Nature: 329: 207,1987}, NK cells {Nature: 362: 458-62, 1993} and monocytes & macrophages { J of Gen Virology: 72: 1401-08, 1991}.

An interesting question: how many XMRV+ are also HHV-6A+ and what might that mean?

Gemini
If you aren't aware of it, check out the HHV-6A Foundation website for more information -- the forums have patient experiences on antivirals.

There are docs out there testing for HHV-6 (no good commercial tests yet to separate A from B) and are waiting for validated XMRV tests to do on their patients. HHV-6A was first found in HIV patients so if XMRV turns out to be a major player, this will not be unexpected as XMRV sounds like an immunosuppressive retrovirus.

Of note: some people with integrated active HHV-6 as proven by PCR and CFS respond to antivirals. HHV-6 Foundation I believe might have been interested in starting a trial with this group.
 

Gemini

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Thanks Hope123 for the info' about the HHV-6 Foundation.

You mentioned HIV, the Lancet reported HIV patients treated with acyclovir delayed progression of HIV-1, indicating herpes antivirals could play a role in a retroviral disease when there's a herpes co-infection.

Another HHV-6 target is worth mention-- vascular endothelial cells {Proc Nat'l Acad Sci USA, 2009 Dec 1: 106(48): 20446-51} where HHV-6 is known to trigger inflammation. It would be nice to know if any of the NMH/POTS+ patients are either XMRV+ or HHV-6+.

Gemini
 
K

_Kim_

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Thanks all - so my instincts were right and this could be quite important for us. Sorry for double-posting - had checked. Looking forward to getting more info.

Thanks for the digestible stats gemini

A bit of history, Dr. Ablashi, a co-author of this paper, co-discovered HHV-6 while working in Robert Gallo's lab at NIH in 1986. Between 1988-1998 he and other researchers published results from 17 CFS studies representing a total of 1473 patients finding on average 64% HHV-6A positive.
I've been trying to keep my ear out for HHV news, but had no idea that the correlations were so strong - 64%.

And thanks for the reminder about the HHV-6A Foundation Hope.

What a crazy disease where I'm hoping to have an AIDS/HIV-like cause found so that I can take serious anti-virals
 

Dr. Yes

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Another HHV-6 target is worth mention-- vascular endothelial cells {Proc Nat'l Acad Sci USA, 2009 Dec 1: 106(48): 20446-51} where HHV-6 is known to trigger inflammation. It would be nice to know if any of the NMH/POTS+ patients are either XMRV+ or HHV-6+.
Hi IF, Gemini and all...

I was one of those 'positive statistics' in Ablashi's CFS studies; he found I had 'acute viremia' with HHV-6. I was not diagnosed with any OI at the time, though nobody really looked.. last year I was dx'd with NMH.

So count me as your first 'statistic'. :D

Back then ('95/'96) everyone assumed HHV-6 was pretty innocuous, except in AIDS. It seems that only recently are scientists realizing how weird and nasty this thing can be... and the more they look, the weirder it gets!
 

wciarci

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Komaroff from B&W in Boston has been studying HHV 6 for some time. There are videos on the web of a 2008 conference on HHV 6. Komaroff presents his finds on HHV 6 and CFS in one video. I'll see if I can find it again. I am HHV 6 positive (per tests from the FFC) but my current doctor doesn't know what to do, hence my trying to get an appointment with Komaroff recently but he is not taking any new patients. I do think there is something to this theory.

Wendy
 

wciarci

Wenderella
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Found some of the links. My understanding of chromosome intertwined HHV 6 is that you have a heavy viral load, literally every cell has the infection as opposed to other normal virus, which is in some cells. Here are some links to the 2008 conference in Baltimore:

http://www.scivee.tv/node/6831

Above, are videos with different presenters.

A description of HHV 6 involvement in CFS: http://www.masscfids.org/resource-l...ess-on-chronic-fatigue-syndrome-research-2008

Perhaps there are multiple paths to ME/CFS. Perhaps the pathway determines how severe the disease is. There may be multiple types and multiple pathways but they all lead to certain irregularities in energy metabolism, endocrine function and neurology.

Wendy
 

Gemini

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Thanks to all for the HHV-6 resources:

Hope123--interesting Annette Whittemore is an HHV-6 Foundation co-founder

Dr. Yes--you are #1!

Wendy--very good video/update. Has Dr. Komaroff commented on XMRV?

The HHV-6 Foundation web site patient experiences with antivirals brings to mind another bit of history:

Twenty years ago I called Glaxo, spoke to the late Gertrude Elion (discovered acyclovir, 1988 Nobel Prize for Medicine) and asked her if it would work against HHV-6. She said no one yet knew. She told me acyclovir was primarlly effective against herpes simplex less so the other herpes family viruses:

HHV-1...simplex 1
HHV-2...simplex 2
HHV-3...zoster(chicken pox/shingles)
HHV-4...EBV
HHV-5...CMV
HHV-6A...associated with CFS/ME
HHV-6B
HHV-7
HHV-8...associated with HIV

Glaxo is still key in herpes antiviral development and their XMRV study announced today is very important.

As for antivirals in the pipeline today, more than a dozen are for herpes simplex, none for HHV-6. PhRMA lists all new antivirals here:

http://www.phrma.org/files/attachments/Infectious Diseases 2007.pdf

Gemini