HHV-6 Hidden in Chromosomes Can Be Passed from Parents to Children

[Kati]

http://www.sciencedaily.com/releases/2010/03/100308151055.htm

ScienceDaily (Mar. 9, 2010)


Human herpesvirus 6 (HHV-6) infects nearly 100 percent of humans in early childhood, and the infection then lasts for the rest of a person's life. Now, a team led by Peter Medveczky, MD, a professor in the Department of Molecular Medicine at the University of South Florida (USF), has discovered that in some individuals, HHV-6 causes such a permanent infection by inserting or "integrating" its DNA into human chromosomes. From this harbor, the viral DNA cannot be eliminated by the immune system.

The paper describing this research was published online March 8 in Proceedings of the National Academy of Sciences.


The USF team also confirmed preliminary results by other investigators that, a long time ago, the virus inserted its DNA into the DNA of human sperm and egg cells. As a result, some people (about 1 percent of people in the U.S.) are born with the virus's DNA in every cell in their body. Indeed, HHV-6 is the first functional virus of any type reported to be passed through the human germ line.


The team presented clear evidence that the virus can insert its DNA specifically into telomeres -- structures at the ends of each chromosome that play key roles in both aging and cancer.


Finally, the team showed that the chromosomally integrated HHV-6 (CIHHV-6) genomes can be reactivated to an infectious form.
The findings are a surprise, since other human herpesviruses cause permanent infection by a different mechanism. The round up their DNA into a little circle that resides inside the nucleus of the cell: they do not insert their DNA into the chromosomes.


There are many unanswered questions that the USF team hopes to sort out. "We would like to know whether the location of the integration has an impact on pathology," Dr. Medveczky said. "We'd also like to know more about which drugs can provoke reactivation in patients that carry this virus in every cell... It would be important for these patients to avoid drugs that may reactivate the virus."
"This is an exciting and provocative series of observations. The questions raised by this work will keep herpes virologists busy for years," predicted HHV-6 expert Phil Pellett, PhD of Wayne State University.


HHV-6 was discovered in 1986 in the laboratory of Dr. Robert C. Gallo at the National Cancer Institute after Gallo asked his co-workers to look for a herpesvirus in AIDS lymphoma cases that might be triggering cancer. "In my mind these findings also should stimulate further studies on a possible role of HHV-6 in some cancers as suggested by others who have found a possible link to some lymphomas," Dr. Gallo commented. "However, clearly more work will be needed to advance any conclusion in this regard."


HHV-6 causes roseola, a generally benign rash and fever in infants. The virus can reactivate in individuals with suppressed immune systems, sometimes causing serious consequences such as encephalitis, hepatitis, myocarditis, and pneumonia.
Recent research has suggested that HHV-6 may also be associated with diseases in people with apparently healthy immune systems: encephalitis, mesial temporal lobe epilepsy, multiple sclerosis, myocarditis, and idiopathic cardiomyopathy. While there is no proof that the virus plays a causal role in these diseases, the virus has been found more often in the diseased tissue than in healthy tissue.


Previous studies had used a visual technique called fluorescence in situ hybridization (FISH), which showed that the viral DNA was present at the same location (near the telomeres) of the same chromosome in both parent and child. This strongly suggested but did not prove that the virus was inherited through the germ line in these children. By determining the DNA sequence of the ends of the chromosome, the Medveczky team clearly demonstrated that the HHV-6 genome was integrated into telomere DNA. The team also showed that HHV-6 DNA, unlike other human herpesviruses, does not curl into a circle inside the nucleus.
The great majority of people, however, do not inherit HHV-6 DNA from their parents and do not have it in every cell of their body. Yet nearly everyone becomes permanently infected with the virus. So Medveczky and colleagues wondered if the virus might take up permanent residence in the body by integrating its DNA into the chromosomes of just some cells.


To examine this possibility, the investigators took cells that had never been exposed to HHV-6 and infected them with HHV-6 that had been engineered to make infected cells glow bright green. Sure enough, once the infection died down, the green cells contained HHV-6 DNA integrated into the ends of the chromosomes. When the investigators stimulated the cells with chemicals known to activate other herpesviruses, cells with integrated viral DNA began producing infectious virus. It will be important to learn whether a similar process occurs during the form of HHV-6 infection that occurs in most individuals.


For the approximately 1 percent of the population born with viral DNA in every cell in their body, several questions arise. Are such people more prone to diseases because they have a greater risk of viral reactivation? If so, which diseases? If a person is born with viral proteins present from birth, would that person's immune system be "fooled" into thinking that the virus was not foreign and need not be attacked? If so, is that a bad thing or a good thing for a person's health? Finally, the virus inserts itself into the telomeres and could theoretically disrupt the function of the telomeres. Since the telomeres are important in cellular aging and in cancer, could the insertion of viral DNA in the telomeres have any effect on a cell's tendency to age or to turn cancerous?


While unique among known human herpesviruses, the capacity of HHV-6 to integrate into human chromosomes is not unique in nature. A herpesvirus that infects chickens, called Marek's disease virus, appears to behave the same way. Interestingly, although the viruses are not otherwise closely related, the DNA sequence used by Marek's disease virus to integrate into chicken chromosomes is remarkably similar to the DNA sequence used for chromosomal integration by HHV-6.
Doctoral student Jesse Arbuckle and research associate Maria Medveczky, both of the USF Department of Molecular Medicine, were lead authors of the study. Other contributing authors were from Bioworld Consulting Laboratories, the HHV-6 Foundation, University of Minnesota, University of Brussels, Stanford University School of Medicine and Harvard Medical School.


The USF study was funded by the HHV-6 Foundation, a non-profit organization that supports virology research, as well as by a grant from the National Institutes of Health.

 

[_Kim_]

Great score Kati! This may be the biggest news since XMRV hit the newstands.

Check out the cast of characters that co-authored this baby:

The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro

Jesse H. Arbuckle, Maria M. Medveczky, Janos Luka, Stephen H. Hadley, Andrea Luegmayr, Dharam Ablashi, Troy C. Lund, Jakub Tolar, Kenny De Meirleir, Jose G. Montoya, Anthony L. Komaroff, Peter F. Ambros, and Peter G. Medveczky

Abstract
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.

p.s. I have the full text version and tried to post it in the Library, but the pdf is too large to upload as one attachment, so it's in two parts

 

[flybro]

Good find Kati

Thanks

 

[Kati]

It is an exciting discovery- and probably very meaningful for ME/CFS. Looking forward to hear the scientists' comments-

 

[_Kim_]

Kati, is it okay if we change the title to 'HHV-6A' instead of 'infectious virus'?

 

[Kati]

Go right ahead Kim, it will be easier to track the article- I just copied and pasted the title of the article in the journal

 

[_Kim_]

Go right ahead Kim, it will be easier to track the article- I just copied and pasted the title of the article in the journal

um, we'll need someone who actually has permissions to do that to make the change.

 

[Kati]

I have done it actually!!!!
You happy with the title or you got another suggestion?

ETA- err I don't think I changed the title in the end, more like the sub-title... Will look out for a mod.

 

[_Kim_]

The HHV-6 Foundation says:

University of South Florida team publishes a landmark study in PNAS

Left to right: Peter Medveczky, Jesse Arbuckle, Maria Medveczky, Shara Pantry
Photo University of South Florida

HHV-6 integrates into the chromosome during latency and reactivates in response to chemical stimulation.
Peter Medveczky and colleagues determined that HHV-6 uses a novel form of latency. The virus finds safe harbor inside the human chromosomes to evade the immune system. Medveczky made this surprising finding by studying patients who have a rare form of HHV-6. They are actually born with HHV-6 integrated into every cell of their bodies, and the virus is passed from parent to child. Many scientists believes that this integrated virus could not be reactivated but Medveczky's group determined that chemical stimulation can cause the integrated virus to start producing.

 

[_Kim_]

Questions Raised by These Studies.

The recognition that HHV-6A achieves latency through chromosomal integration raises important questions.

• Can HHV-6B and Mareks disease virus, a herpesvirus of fowl do the same, as suggested by FISH data.
• What are the molecular switches that dictate whether, following new infection in a cell line capable of sustaining productive lytic infection, the virus instead integrates and establishes latency?
• What are the switches that activate transcription? Does transcription always lead to production of full virions? If not, might the production of selected viral proteins have pathogenic potential, as appears to be the case with endogenous retroviruses?

snip

The documentation of inherited HHV-6 also raises important questions.

• Is the immune system of patients born with HHV-6 tolerant of any viral antigens? Given that the viral genome is present in every cell and capable of producing competent virions, are these patients at particular risk for any diseases?
• Are the patients susceptible to superinfection with another strain of HHV-6A, or to infection with HHV-6B?

Answers to these questions await further study.

 

[Mark]

Science Daily wonders:
"Since the telomeres are important in cellular aging and in cancer, could the insertion of viral DNA in the telomeres have any effect on a cell's tendency to age or to turn cancerous?"

Can I ask the scientists on here: is it conceivable that the viral DNA could insert itself into the telomeres in such a way that rather than making a cell age more quickly, the insertion could somehow acts as a stopper to the gradual attrition of telomeres? In other words, cells with viral DNA inserted might survive longer because once the telomeres are worn down to the point where the viral DNA is, that bit effectively protects itself from getting deleted? I'm sure it doesn't work quite like that, but that's why I'm asking...

Because if the telomere insertion could work in that way, it might be time to look up that old thread called something like "Does anyone else look young for their age?"...

 

[natasa778]

This is actually not news as was 'discovered' few years ago by a Japanese team and then confirmed by a British-led team... this says a lot about media reporting... Not my intention to spoil the joy as it is really great and I'm looking forward to more about this. Great that this type of research is happening and also great that it is finally getting reported!!

 

[Athene]

Is this integration with the chromosomes the same thing that XMRV does?
Is anyone clever enough to understand if this has implications for XMRV research in terms of transmission etc?

 

[bullybeef]

This is really freaky. Both my young sons have had these forms of rashes, my youngest only last week, and I had a widespread rash about a year before I left work (2004). I forgot what my GP said it was, but upon looking at some pictures, I found it. And low and behold it was infectious mononucleosis: http://en.wikipedia.org/wiki/File:Cross_Reaction_Rash.JPG

I can't believe how many links I am finding. I also had some blood tests done recently, and the practice nurse didn't do a infectious mononucleosis test (I'd like to think she either didnt know I once had it, or simply forgot).

It is really interesting to discover exactly what could have activated my illness.

 

[Dr. Yes]

This is actually not news as was 'discovered' few years ago by a Japanese team and then confirmed by a British-led team...

That previous research was on what was called Chromosomally Integrated HHV-6 (the name may have to be modified now!) or CIHHV-6, which referred to a relatively rare condition that indeed has been known about for a few years...from the HHV-6 Foundation website:

"In rare cases, HHV-6 i found to be integrated into human chromosomes in high copy numbers producing unusually high viral loads in the whole blood and serum. Both HHV-6A and B have been found integrated into the chromosomes of immunocompetent patients at persistently high levels of viral DNA in blood, sera, and hair follicles (Ward 2006). A large study in Japan showed that the incidence is 0.2% but two smaller studies from the UK suggest it may be approximately 0.8 and 1.5%. Children hospitalized for seizures or encephalitis have higher rates of CIHHV-6, reported to be 2.9-3.3% (Leong 2007)."

But the very surprising new (though preliminary) finding in this study is that HHV-6 does not appear to use the normal form of latency for herpesviruses at all, but instead always integrates into host chromosomes. As their abstract concludes:

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.

Other herpesviruses go into latency in our cells by hiding small circular packets of DNA in our nuclei. Apparently this was assumed to be true of HHV-6 (and I find it surprising that no one bothered to look??), but it turns out - from this one study at least - that there is no evidence of episome formation in HHV-6 infected PBMC's or deliberately infected experimental cell lines.... Instead, in both cases the virus integrated itself into the telomeres of certain chromosomes, and could be re-activated chemically:

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...

Anyway, since those chemicals could induce chromosomally-stored HHV-6 (both from newly infected cell lines and from the blood cells of CIHHV-6 patients) out of latency and to produce virions, this is probably not a "benign" storage of HHV-6 in chromosomes in either case. (Previously there was debate about whether CIHHV-6 could replicate at all.)

(from natasa778):

Great that this type of research is happening and also great that it is finally getting reported!!

Yes! Dr. Ablashi has been complaining for years about the lack of interest in and poor funding of HHV-6 research by the NIH (for whom he worked), etc; remember his testimony at the November CFSAC meeting? Hopefully now things will start to change.

(from Athene):

Is this integration with the chromosomes the same thing that XMRV does?
Is anyone clever enough to understand if this has implications for XMRV research in terms of transmission etc?

XMRV integrates into the genome itself, while HHV-6 only does so in the telomeres (bits of non-coding DNA at the ends of the chromosome). The telomeres have no genes, and so are mostly ignored until a cell divides, when most (but not all) of the telomere is copied along with the rest of the chromosome.

I don't see how this particular finding would relate to XMRV research, unless one speculation that has been thrown out there - that a retrovirus can somehow get integrated into the genome of HHV-6 - turns out to be true. However, that is a pure speculation by one guy (I think a pharmaceutical company scientist), as far as I know. Of course, I'm not what one would normally call 'clever'! <---(me)

From bullybeef:

This is really freaky. Both my young sons have had these forms of rashes, my youngest only last week, and I had a widespread rash about a year before I left work (2004). I forgot what my GP said it was, but upon looking at some pictures, I found it. And low and behold it was infectious mononucleosis: http://en.wikipedia.org/wiki/File:Cr...ction_Rash.JPG

The rash depicted there is a cross-reaction rash that people with EBV infectious mononucleosis develop when taking most types of antibiotics at the same time. That particular rash isn't caused by the virus alone, and I don't know if such cross-reactions take place with HHV-6 or CMV and antibiotics. Were you and your sons all on antibiotics when you developed these rashes?

Infectious mononucleosis (which technically is EBV, though CMV can cause something very similar) itself can cause a rash, though I don't know how it presents (you've probably found out by now!). HHV-6 variant B is well known to cause a particular kind of rash called roseola in children age 2 years or younger. But to my knowledge only immunocompromised adults can get a rash from HHV-6.

 

[bullybeef]

Thanks Doc for the info, it's beginning to make perfect sense. Let me elaborate:

My eldest son had, what our GP suggested, a very rare rash condition. I have been racking my brain to recall it and I've just found it on the net. It was Henoch–Schnlein purpura. It was only the 2nd time my GP had ever treated it. But we did have a particular issue. My son only has one kidney, and HSP can have a negitive effect on the kidneys. So he was in hospital for a week, whilst the doctors tried to work out what was wrong with him, and how to treat him. He also had baby arthritis. So, although my memory is vague, he was on antibiotics because of this (I think it was intravenous). If you look at HSP on Wikipedia, right at the bottom it gives William Osler a mention. Scary or what?!!

When I had mononucleosis, again it is very vague, but I think I was also on antibiotics. Has this info been passed onto my ME consultant? Did this lead to my diagnosis? I have no idea.

My youngest son has just got over herpes simplex virus, but there is another rash occurring. That is why I have been looking into it. The scary thing is, this new rash does look like HSP!!

 

[natasa778]

The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors.

A lesser-recognized form of human herpesvirus 6 (HHV-6) persistence is integration of the viral genome in a host chromosome and high viral copy numbers in blood or sera are characteristic of this phenomenon. A cross-sectional study was performed to determine the frequency of high HHV-6 viral loads in whole blood (>6 log(10) copies/ml) in a population of blood donors in London, UK. Blood samples from 500 anonymized blood donors were collected from one donation center, DNA extracted, and quantitative realtime PCR used to measure viral load. Four samples (0.8%) were found to have high viral copy numbers of HHV-6 (median 6.7 log(10) copies/ml; range 6.5- 6.9 log(10) copies/ml). Cellular DNA was also quantitated using qRT-PCR for beta-globin. By comparing these two results, we calculated that there were between two and five copies of HHV-6 present per cell in these four donors. The median viral load detected in plasma from the four individuals was 3.8 log(10) copies/ml (range 3.5-4.0 log(10) copies/ml). All samples were HHV-6 variant B. In addition, a retrospective analysis of all diagnostic blood samples performed for HHV-6 in our center showed a prevalence of 2.9% of high viral loads characteristic of integration. In conclusion, high viral copy numbers of HHV-6, representing a population of viral integration, is detected in 0.8% of UK blood donors. The presence of high HHV-6 viral loads in healthy normal individuals reiterates the need to consider the confounding effect of HHV-6 viral integration in any laboratory diagnosis of HHV-6 infection.
Leong HN, et al Division of Infection and Immunity, Centre for Virology, Hampstead Campus, Royal Free and University College Medical School, London, UK. J Med Virol. 2007 Jan;79(1):45-51.

 

[Dr. Yes]

Btw bullybeef I edited that part of my post while you were posting: I did remember that EBV can cause a rash by its lonesome, and double-checked on a couple medical sites... it's usually not an itchy rash like the antibiotic-reactive one, though.

Oh, and in case it hasn't been ordered by your son's doctor yet, it's a good idea to do urinalysis in HSP cases, looking for blood or protein in the urine, as kidney damage/ disease is sometimes caused by it. Though that happens more often in adults than in kids. Just something you might want to keep your eyes on.

 

[bullybeef]

Btw bullybeef I edited that part of my post while you were posting: I did remember that EBV can cause a rash by its lonesome, and double-checked on a couple medical sites... it's usually not an itchy rash like the antibiotic-reactive one, though.

Sorry, I understand you now. No, I don't think any of us were on antibiotics prior to the rashes. And you are correct, I don't recall the mono I had being persistently itchy. What was weird was the speed it cleared up. It started as a blemish on my chest, and after week, my whole torso and thighs were covered, yet it was gone in a couple of days.

Oh, and my eldest was in hospital on two separate occasions for his arthritis and HSP.

 

[JillBohr]

Thank you Kati! I have been following the HHV6 Foundation off and on the last year. My oldest son has autism and seizure disorder. According to their website, lamotrigine, is effective against HHV6-B but not HHV6-A. My son takes it (aka lamictal) for his seizures. http://www.hhv-6foundation.org/treatment.htm

Oh, btw, my kids also come down with the strangest skin rashes. My youngest son was diagnosed with Pityriasis rosea just last December. It still hasn't cleared up all the way and it is now March.