HERVs Expression in Autism Spectrum Disorders

[natasa778]

open access ....

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048831

Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.
Methods

The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.
Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.
Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

 

[redo]

Thanks for posting Natasa. I really think the discovery of activated HERVs and it's pathogenic role in various diseases will be the next revolution in medicine.

 

[natasa778]

just found this, interesting

HERV-H (its env gene!) is the one just found overactivated in autism…


http://www.ncbi.nlm.nih.gov/pubmed/20422298

In humans, exogenous retroviruses are known to cause immunodeficiency and neurological disease. While endogenous retroviruses are firmly established pathogens in other species, the human endogenous retroviruses (HERVs) may well be considered as emerging pathogens. HERVs also exhibit complex interactions with exogenous retroviruses and herpesviruses. Two neurological disorders in particular are associated with HERVs: multiple sclerosis (MS) and schizophrenia. HERV-H/F and HERV-W are specifically activated both in the circulation and the central nervous system (CNS) in a majority of MS patients, and particularly, the envelopes (env transcription and Env proteins) appear strongly associated with disease activity. Interferon beta (IFN-beta) therapy is well-established for MS. IFN-beta is also known to have anti-retroviral activities toward exogenous retroviruses (HIV and HTLV-I).

New reports show that IFN-beta also mediate down-regulation of HERV-H/F and HERV-W in MS patients. ..

 

[natasa778]

also this, esp interesting as they found the level of HERV-H expression correlated to severity of autism symptoms

B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity.

These findings indicate that both HERV-H Env and HERV-W Env are expressed in higher quantities on the surface of B cells and monocytes in patients with active MS, and that the expression of these proteins may be associated with exacerbation of the disease.

 

[anciendaze]

Note that HERV-K is not found at higher levels of expression in ASD. This has been positively correlated with schizophrenia, with typical onset after puberty. HERV-K is also more often expressed in human cells infected with HIV. (This might even be used to distinguish infected cells.) Recall that the old name for schizophrenia was dementia praecox, and that there is AIDS-related dementia associated with HIV. This seems tied to neurodegenerative diseases, which are different from ASD.

HERV-W is typically active in the formation of the placenta and gestation, even when the resulting children are healthy. Finding this still active later points to something derailing normal development prior to birth.

HERV-H is of special interest to me because the envelope has immuno-suppressive properties. This could be associated with immunological abnormalities in a number of diseases.

HERV-E is still somewhat mysterious, and does not appear highly correlated here.

All four are more likely to be active in leukocytes or in specific cancers.

There are plenty of arguments used to ignore the role of HERVs in disease. Mostly these amount to saying "we aren't interested in them". Dealing with the complications they introduce is definitely harder than following the spread of a single pathogen not present in healthy people.

Is there a sharp distinction between endogenous and exogenous retroviruses? Not in the case of MMTV or JSRV. In fact the best way to resurrect a defective ERV is to introduce a very similar retrovirus which is replication competent. In this environment it is easy for ERVs transcribed under the same conditions to recombine with exogenous retroviruses and regain competence. Because the ERVs are already present in essentially every somatic cell they have an overwhelming advantage in terms of cell population genetics within an individual. Wait long enough and it may be impossible to identify the wild-type virus which initiated the process.

Another argument covers exogenous retroviruses which infect cells in vitro, but usually fail to infect intact hosts. Infectious disease specialists pushing this line of reasoning say those retroviruses can be safely ignored. The catch comes when hosts are not fully immune competent. (This can come about as the result of an unrelated disease, as could have happened to many of us with sudden onset.) There is a major loophole in the argument when talking about infants: all human infants start out immunologically naive. In a number of animal models of retroviral infection the viruses are commonly transmitted to neonates via milk. In the case of HTLV-1 this is also a significant route of human infection.

If we are talking about chronic conditions which start either around birth or under situations where the immune system is challenged those arguments above about ignoring retroviruses may not be valid.

 

[natasa778]

HERV-H is of special interest to me because the envelope has immuno-suppressive properties. This could be associated with immunological abnormalities in a number of diseases.

...
If we are talking about chronic conditions which start either around birth or under situations where the immune system is challenged those arguments above about ignoring retroviruses may not be valid.

Thanks!

Do you think that this "intrinsic potential of PBMCs from ASD patients to express HERV-H after stimulation in culture" could offer some clues?

In summary, therefore, the results pinpoint two distinctive features of HERV elements in ASD: i.e. a significant overexpression of HERV-H, paralleled by a significant down-regulation of HERV-W in PBMCs from ASD patients compared to controls. Moreover the analysis of individual patients and controls highlighted an intrinsic potential of PBMCs from ASD patients to express HERV-H after stimulation in culture

 

[anciendaze]

Yes, easy expression of HERV-H in PBMCs does point to immunosuppression, which has been documented in other laboratory studies. Whether this is due to a reactivated HERV-H being held latent or another latent virus stimulating transcription of HERV-H is unclear. It might even be due to small genetic differences in components of the immune system holding retroviruses latent. As I've said elsewhere the immune system has a defense in depth against them with many layers. I doubt we even know about some defenses at present.

What we do not see at present are the massive genetic differences researchers once expected to find in ASD. Patterns of inheritance suggesting genetic defects could also be attributed to persistent infectious disease passed from parent to child. This could take place in the womb, if a retrovirus crosses the placenta, or in the perinatal period, as I have suggested in talking about transmission via milk. Genes inserted in chromosomes can even arrive via sperm.

I don't think it is safe any more for researchers to assume all genes arrive via Mendelian inheritance. The statistical association with the age of the father could be tied to accumulated genetic defects, as usually assumed, but the probability of chronic infection also increases with age. When dealing with viruses which insert their own genes in chromosomes you can't easily discount infection. The assumption this doesn't happen because we don't know of any such infection leads to circular reasoning. If the etiology is unknown we must consider the possibility of undetected pathogens.

 

[natasa778]

Yes, easy expression of HERV-H in PBMCs does point to immunosuppression, which has been documented in other laboratory studies. Whether this is due to a reactivated HERV-H being held latent or another latent virus stimulating transcription of HERV-H is unclear. It might even be due to small genetic differences in components of the immune system holding retroviruses latent.

This is new and 'interesting'


Ancient Viruses Wreak New Havoc

http://www.the-scientist.com/?articles.view/articleNo/32990/title/Ancient-Viruses-Wreak-New-Havoc/

"...Though researchers had suspected that ERVs could reactivate and recombine, the study provides direct evidence of such an event, says immunologist David Markovitz of the University of Michigan, who was not involved with the study. “It’s extremely interesting that the mice activate or reactive their expression of ERVs in the absence of antibodies, ...

Previous data have indicated that signals from bacteria in the mouse gut could lead to increased EVR expression, but that antibodies usually block those microbial signals. Thus, Kassiotis’s team hypothesized that in the absence of such antibodies in their immunodeficient mice, invading microbes could activate ERV expression. Indeed, when placed in germ-free environments, or fed acidic water that would limit their gut microbes, the immune-deficient mice experienced less viral reactivation…"

If confirmed in humans this would put together most pieces of the puzzle in autism, and probably ME! The plot thickens indeed. Now whether anyone will be bothered enough or brave enough to investigate in depth is another matter.

Note the trigger happy not-happening-in-humans resident denialist is already on the case, having 'the last word'

 

[anciendaze]

I notice once again that no one is talking about thresholds of detection. The antibody response depends on clonal expansion of B-cells to amplify tiny signals into a substantial response. The idea that an infection might lie below the threshold of detection, then be boosted to the point of detection by clonal expansion, just isn't considered.

There is no question both mice and humans are exposed to a wide variety of exogenous retroviruses. Defenses against these can operate by destroying virions, or by blocking replication at a number of later stages. For those viruses which target B-cells, and can replicate provirus via host-cell mitosis, exploiting immune response to unrelated pathogens is an attractive strategy which bypasses many defense mechanisms. If tiny numbers of cells harbor latent infections in healthy individuals the whole business of resurrection of similar ERVs via recombination becomes much easier to understand, and need not require wildly improbable events.

There is an aspect of probability here which causes great confusion. Every recombination event is improbable. If you insist on the production of a specific genome you can easily argue that this would never happen again in human history. The criteria for production of any replication-competent genome are much broader and harder to pin down. Starting with a single replication-competent provirus is not likely to lead to a specific genome, but the probability of producing some replication-competent genome, starting with another replication-competent genome, is reasonably high.

I think there is considerable evidence that resurrection of defective ERVs takes place more often than commonly assumed. If the literature already holds dozens of examples assurances about the improbability of future events ring hollow.

 

[currer]

What an interesting discussion.

I remember a paper recently which surveyed autistic patients for genetic similarities - and could find none.
there did not seem to be a genetic type that could be shown to be predisposed to developing autism.

http://www.ncbi.nlm.nih.gov/pubmed/22843504
http://blog.23andme.com/health-traits/autism-study-reveals-no-genetic-associations/
http://arstechnica.com/science/2012...new-mutations-many-genes-behind-the-disorder/

 

[natasa778]

Isn't B Huber at Tufts (of xmrv-coffin fame) looking at HERVs expression in ME? I don't remember details but think it was HERV-K she was focusing on... anyone?

 

[natasa778]

found this bit of info:

She has studied the presence of retrovirus HERV K-18 as a marker for those who might develop ME/CFS after an acute infection such as mononucleosis. Her research shows that EBV induces the HERV K-18 envelope gene to trigger the expression of a specific superantigen and that there are more HERV K-18 alleles in post-mono ME/CFS patients than in controls.

http://www.investinme.org/BrigitteHuber.htm

that study was well under way 2 years ago, not sure what happened to it

http://www.cfids.org/cfidslink/2007/100303.asp

 

[natasa778]

What we do not see at present are the massive genetic differences researchers once expected to find in ASD. Patterns of inheritance suggesting genetic defects could also be attributed to persistent infectious disease passed from parent to child. This could take place in the womb, if a retrovirus crosses the placenta, or in the perinatal period, as I have suggested in talking about transmission via milk. Genes inserted in chromosomes can even arrive via sperm.

I don't think it is safe any more for researchers to assume all genes arrive via Mendelian inheritance. The statistical association with the age of the father could be tied to accumulated genetic defects, as usually assumed, but the probability of chronic infection also increases with age. When dealing with viruses which insert their own genes in chromosomes you can't easily discount infection. The assumption this doesn't happen because we don't know of any such infection leads to circular reasoning. If the etiology is unknown we must consider the possibility of undetected pathogens.

We keep hearing about those mysterious 'de novo' gene mutations popping up in autism (as well as 'healthy' control population) ... copy number variations ... deletions, duplications, chromosomal rearrangements...

Time for some fresh perspective on all that ?

A recurrent translocation is mediated by homologous recombination between HERV-H elements

... Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation ...

 

[Daffodil]

my friend with CFS had his blood tested for HERV-k18 and was found to have only slightly elevated levels...or slightly elevated antibodies...or something. nothing significant, I am told.

isn't it one of the HERV-W's that is thought to cause CFS?