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Wednesday 5 April 2023

A virus as a trigger for some Cancer, most Multiple Sclerosis (MS) and perhaps some Autism


 


Mexico is the world's largest exporter of beer, and it's not just Corona

Not many years ago you would have been considered mad to suggest that a virus could trigger cancer, MS or some autism.

We now have a vaccine to prevent cancers triggered by the human papillomavirus (HPV). Young people aged 9 - 26 are offered this vaccine in many wealthy countries.

It is believed that the Epstein-Barr virus (EBV) contributes to about 1.5% of all cases of human cancer.

 

Epstein-Barr Virus and Cancer

 

EBV causes mononucleosis (IM, mono), also known as glandular fever. A commercial vaccine does not yet exist but is thought to be achievable.

Multiple sclerosis (MS) has long been thought to have a viral trigger. I have been reading about impaired myelination for 10 years and it takes a very long time for ideas to get confirmed.  In the case of MS it is again the Epstein-Barr virus. Almost all adults have been exposed to this virus and most people do not develop MS.  The science suggests that multiple events are needed to trigger MS, but that a required one is the presence of this virus.  That would suggest that if children were vaccinated against EBV, they could not go on to develop MS later in life.

 

Epstein-Barr virus may be leading cause of multiple sclerosis

 “The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said Alberto Ascherio, professor of epidemiology and nutrition at Harvard Chan School and senior author of the study. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”

 

Recall that MS is one of those diseases that is very much more prevalent in females than men.  It is the opposite of autism.

The science is moving on and now has got the point of explaining why EBV can cause cancer.  The actual biological pathways have been proposed.

 

Signaling pathways of EBV-induced oncogenesis

 

One of several examples is EBV-induced oncogenesis through the PI3K/AKT signaling pathway.

 



 

EBV-induced oncogenesis through the PI3K/AKT signaling pathway. LMP1 and LMP2A promote angiogenesis through the PI3K/AKT/HIF-1α/CCL5 signaling axis and the PI3K/AKT/mTOR/HIF-1α signaling axis, respectively. LMP1 inhibits PTEN through miRNA-21 and enhances the PI3K/AKT signaling pathway to promote the formation and proliferation of CSCs. EBV-miRNA-BART7-3P can also promote the high expression of β-catenin by inhibiting PTEN, leading to EMT

 

Regular readers may notice overlaps with what we have seen in autism. The same pathway can lead to autism.

Here is a recent autism paper on this same pathway.

Targeting PI3K-AKT/mTOR signaling in the prevention of autism


 The role of viruses in autism

Now we have established that medicine accepts that a virus can play a role in triggering cancer and that science points a finger at a virus being a trigger for MS, it is not so crazy to think about the role viruses might play in some autism. 

 

The easy part – Maternal Immune Activation (MIA)

We have clear evidence that if a pregnant mother’s immune system is activated during pregnancy the incidence of autism rises.  In this case it is the immune response that causes the problem, rather than the specific virus.

 

Virus specific

One very damaging virus, spread by mosquitos, is Zika. If a mother is infected  during pregnancy it may lead to microcephaly (small head), brain damage and joint/muscle malformation in her child.

 

Endogenous retroviruses

It has been suggested in the research for many years that endogenous retroviruses play a role in autism.

Human endogenous retroviruses (HERVs) are DNA sequences within human chromosomes; they comprise 1 to 8% of the human genome.  HERVs represent footprints of previous retroviral infection and have been termed “fossil viruses”.

 

Demystified . . . Human endogenous retroviruses

Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits. However, several HERVs have been implicated in certain cancers and autoimmune diseases. This article demystifies these retroviruses by providing an insight into HERVs, their means of classification, and a synopsis of HERVs implicated in cancer and autoimmunity. Furthermore, the biological roles of HERVs are explored.

Take home messages

o   Human endogenous retroviruses (HERVs) make up part of our genome and represent footprints of previous retroviral infection

o   HERVs possess a similar genomic organisation (gag–pol–env) to present day exogenous retroviruses but are not infectious

o   The HERV-K superfamily represents one of the most active HERVs and is capable of producing retroviral particles

o   HERVs may be of benefit to the host but could also be harmful, and may be involved in certain autoimmune diseases and cancers

 

I came across this article recently: 

Could an Ancient Virus Be a Genetic Driver of Autism?

Genome and transcriptome analysis revealed BTBR autism mouse models have increased levels of endogenous retrovirus genes. BTBR/R models of ASD showed differences in the expression of a variety of genes that are indicative of endogenous retrovirus activation. BTBR/R mice exhibit autistic-like behaviors without reduced learning abilities. 

Overall, the study revealed that retrovirus activation causes the copy number variants in BTBR mice to increase, which leads to the differences in behavior and brain structure seen in BTBR/J and BTBR/R mice. 

Further Developments 

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the usefulness of the other lineage of BTBR/R mice because they exhibit autistic-like behavior without compromised spatial learning ability. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. 

Furthermore, it is necessary to classify autism subtypes according to their onset mechanism, which is a vital first step towards opening up new avenues of treatment for autism.

 

Here is the full paper, which comes from the RIKEN Brain Science Institute in Japan, which has been mentioned in a previous post.

 

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

 


Hyper-activation of ancient retroviral infection accelerates host genome evolution toward ASD susceptibility by increasing the chance of CNV formation. The accumulated genetic variations lead to the divergence of autistic-like behaviors in both BTBR strains. Active ERV also recapitulates the viral infection process of ISR pathway invasion and IRES-mediated translation, which changes the global transcriptome during embryonic development in BTBR mice. BTBR/R has severer core symptoms of autism and wildtype Draxin expression, which suggests BTBR/R is a valid autism model with unaffected forebrain bundles.

 

There have been previous studies looking into ERVs and autism.

 

Children With Autism Spectrum Disorder and Their Mothers Share Abnormal Expression of Selected Endogenous Retroviruses Families and Cytokines

 

Human Endogenous Retroviruses in Autism Spectrum Disorders: Recent Advances and New Perspectives at the Gene-Environment Interface

Human endogenous retroviruses (HERVs) are genetic elements, derived from their exogenous retroviral counterpart by a process of germline infection and proliferation within the human genome, and their integration as proviruses led to the fixation and the vertical transmission, following Mendelian laws. HERVs currently make up ~8% of the genetic material, and some of them have been cooped for physiological functions. Otherwise, their activation in response to environmental factors has been associated with human pathological conditions. In the setting of neurodevelopmental disorders, HERVs have been proposed as contributing factors involved in Autism Spectrum Disorders (ASD), spanning the bridge between genetic susceptibility, environmental risk factors and immune response. We described a distinct expression profile of some HERV families and cytokines in lymphocytes from autistic children and in their mothers suggesting a close mother-child association in ASD. Moreover, in vitro treatment with an antiretroviral drug was able to restore the expression level of HERVs and cytokines providing new insights into the potential role of HERVs as biomarkers of ASD and raising the possibility of using HERVs expression as a therapeutic target for a tailored approach to patient care.

  

Conclusion 

We know that some cancer is preventable via a vaccine blocking the progress of a virus, hopefully more types of cancer will be prevented in future.

Some of the suggested modes of action for the Epstein-Barr virus (EBV) to cause cancer do involve pathways that are very relevant to autism.

It appears that an effective EBV vaccine might protect women (and some men) from developing multiple sclerosis (MS).  Will it also have the effect of reducing their chance of giving birth to a child with autism?  Time will tell.

Any kind of illness, viral or other, may trigger an exaggerated immune response during pregnancy and increase the incidence of autism.  This is the basis of one of the common animal models of autism, called Maternal Immune Activation (MIA).

The human endogenous retroviruses  (ERVs) accumulated as junk in our DNA do appear to be able to affect gene expression leading to cancer, autoimmune disease and indeed some autism.

The Japanese researchers from RIKEN suggest that it may be possible to develop new treatments for autism that suppress ERV activation.

One logical question is whether viruses are relevant just to causing autism or its ongoing level of severity.

In the case of cancer and MS it looks like the virus is primarily involved in triggering the disease.  Once the process has started, the benefit from suppressing the virus may have passed. 

Can existing antiviral drugs treat some autism?  Antiviral drugs work just for specific viruses and they just suppress them, rather than eliminating them.

The antiviral drug Valtrex has long been used by some doctors to treat autism in the US. Just Google it and you will find enthusiasts like parent Jenny McCarthy -- “when we started him on Valtrex, speech started pouring out of him”.  There have been no clinical trials.

This is an area where more research genuinely is needed. Hopefully the RIKEN Brain Science Institute will translate their ERV findings into approved therapies.  That is what is supposed to happen, but usually does not when it comes to autism.

Autism is nowadays such a broadly defined diagnosis, just about anything might have caused it. Autistic behaviors have been caused by a bacterium, a fungus/mold and very possibly a virus.  If only it was as straightforward as understanding and treating MS.






41 comments:

  1. Hi Peter,
    Your article reminds me of a mother on FB who’s doctor tested for Herpes Simplex Virus and subsequent treatment showed some improvement.

    Searching online shows the link has been proposed previously.

    The craziest article I found was of a man who regressed in Autism at age 41. Talk about late regression. Definitely a unique case but it does show what is possible.
    https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.1991.tb14804.x

    ReplyDelete
  2. We used malarone with great effect for a time and foe the past year we used valtrex. it was introduced because she was always having some herpes virus active (pcr positive). we now have no more herpes active but we have a problem: if we stop valtrex for even a day she gets worse. we even accidentally blind studies this because twice now we forgot to add valtrex to her weekly pill organizer and by day 4 we were despairing as to what has happened to make her regress so much. it takes weeks to get her back to where she was, with such a 4 day break.
    I can also say that gut biopsies from asd kids come back positive with some weird viruses (pcr).

    ReplyDelete
    Replies
    1. Hi Tatjana, I remember your posts on the positive effects of Malarone after speaking with the Brazilian mother. I spoke to her doctor, but he is keeping his cards close to his chest, but he did say he’s getting some good results on ASD kids using a Lyme disease protocol, even when they are not infected.
      Where did you get the gut biopsy? My daughter has high basophils which according to our Dr is a sign of low vitamin D. But the hospital who checked her blood said it can also be parasites. I’m looking for the best place to get her checked out.

      Delete
    2. We are working with dr Krigsman. Parasites are an easily silved problem; just do a combined protocol as if your kid does have them. In many cultures people do that for kids once a year without checking - its very safe medication. I think pyranthel
      something is the best one?

      Delete
    3. Hello Tatjana, please tell me about valtrex. You said that if you stop it things get worse, we also want to try valtrex. Can you tell us more about the administration and the child's condition? Thank you and I await your reply

      Delete
  3. Bumetanide ( loop diuretics) and ponstan fun facts with viruses

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350920/

    -Stephen

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  4. Sporanox and viruses

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455256/

    ReplyDelete
    Replies
    1. Antifungals as antivirals, interesting.

      Delete
    2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544934/

      Also, interesting.

      Delete
    3. ERK pathway HERV

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501692/

      Delete
    4. Anonymous (Stephen?)
      Please add a sentence (or rather three) on what the link is about, it increases the interest for the paper and is helpful when searching for the specific info later on.
      Thanks!
      /Ling

      Delete
    5. No problem, I can definitely do that to help the group.

      -Stephen

      Delete
  5. I'm still fascinated about the different ways COX-inhibitors have a cognitive effect in different disorders. I was a bit surprised to find Ibuprofen mentioned in this article on SUDEP and found it even more interesting that the effect was not on seizures but on the resulting vasoconstriction:

    "we demonstrate for the first time that acute and chronic administration of the COX-2 inhibitor, ibuprofen, or the L-type calcium channel (LTCC) blocker nicardipine, which block postictal vasoconstriction via different mechanisms, significantly extended the life of mice in an acute and chronic model of seizure-induced premature mortality without reducing seizure frequency and thus provides a proof-of-principle that SUDEP has a vascular component. Our results also provide pre-clinical evidence that targeting the enzyme COX-2 or LTCC's may be a potential therapeutic strategy for those at risk for SUDEP.
    https://www.sciencedirect.com/science/article/pii/S002839082300103X (paywalled)

    /Ling

    ReplyDelete
  6. Hi Peter,

    Here is a cool app my psych friends use. It's called NEI prescribe, it is expensive but I thought it might be useful to the group.

    https://www.neiglobal.com/Members/NEIApps/NEIPrescribeOverview/tabid/450/Default.aspx

    -Stephen

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  7. Lithium has anti viral properties. We just increased my son’s dose after having his first manic episode in 5 yrs. He’s still on a low-ish dose - none of the scary side effects either that people assume automatically come with lithium. I was hospitalized with flu/pneumonia in my first trimester pregnancy with my son - so likely MIA autism . I’ve never met any parent who had luck with valtrex - I wish it was that simple
    ~Tanya

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  8. Hi Peter, I have been scouring this blog for hours. I am trying to find the link for the intranasal glucose/insulin spray a father from Romania?/Bulgaria created for his son. I can't find the links now. I think this will benefit a subset of children with MSUD disorder--maybe not the MSUD disease but, the disorder. There was a link to his site, as well as, in the comment section. I just can't find the post. Any help will be greatly appreciated! BTW: Congrats on the book-Great job as always!

    ReplyDelete
    Replies
    1. The best way to search within the blog is actually to use Google and tell it to only look in this blog.

      For example, enter into the google search box:-

      intranasal insulin "site:epiphanyasd.com"

      there are 76 results.

      Delete
  9. This comment has been removed by the author.

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  10. Hi Peter,

    Here is a great article about covid viral proteins and brain fog.

    https://www.biorxiv.org/content/10.1101/2023.04.04.535604v1

    -Stephen

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    Replies
    1. Interesting, and it is the same pathway P13K-AKT mentioned in the above post, which is involved in both cancer and autism.

      Delete
    2. Agreed. I looked more into that pathway last night.

      Here is how it relates to ASD.

      https://www.sciencedirect.com/science/article/abs/pii/S0736574814000409

      Furthermore, look up Rhoa and Bumetanide.

      https://pubmed.ncbi.nlm.nih.gov/34687399/

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225311/



      Delete
  11. https://www.nature.com/articles/s41598-022-15551-6

    Over the counter way to block Pi3k-akt-mtor. I personally like Aurora Liposomal Vit C and have used it in the past.

    -Stephen

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  12. Also, naltrexone is now available over the counter in the United States.

    https://pubmed.ncbi.nlm.nih.gov/33540155/

    It also blocks the same pathway.

    ReplyDelete
    Replies
    1. Naltrexone requires a prescription in the United States, online telemedicine prescriptions are still prescriptions. I'm sure there's ways to get it without a prescription but it's still legally supposed to have one

      Delete
    2. FDA approved Narcan nasal spray otc recently. You just have to ask your pharmacist for it.

      https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray

      In Michigan you can get it from vending machines for free. Easy enough to run a small trial to see if it works.

      -Stephen

      Delete
  13. Peter help me translate this: is Clonazepam effective in this scenario (MIA) only if used as soon as possible?
    https://www.sciencedirect.com/science/article/abs/pii/S0006295221003270
    Did I miss the boat in this one - my son is now 23. I commented in this thread recently about his manic episode (I.e. awake for 36 hrs, he is not aggressive) and trying small increase lithium but now wondering about Clonazepam add-on?
    ~Tanya

    ReplyDelete
    Replies
    1. Low dose clonazepam has been covered in this blog. It is well worth a trial because it is extremely safe and very cheap. There is a liquid form which allows you to measure very small doses. It may give a cognitive boost, it does not reverse autism.

      Mouse models are interesting and many have a rescue therapy to reverse them. It is not so simple in humans.

      The dose is so small there will be no anti-anxiety effect. The drug has a long half life so it takes 3 days to reach its peak level in the blood stream. The therapeutic dose is quite precise and outside this zone there is no cognitive gain. Due to interactions with other therapies you may have to adjust dosing to find the effective one. This will be much easier with the liquid form.

      Delete
    2. Thanks for the assistance, Peter. I did read your posts on Clonazepam years ago but at the time didn’t have a doctor willing to prescribe. Yes mouse models… more interested in rescuing from psychiatric co-morbidity (manic episodes/“bipolar”) than reversing autism at this point.
      ~Tanya

      Delete
    3. Tanya, has your son be given an antipsychotic for hypomania?

      Apparently hypomania is quite common in young adults with autism and of all levels of autism?

      Delete
    4. Yes the hospital that diagnosed bipolar 5 yrs ago prescribed olanzapine and an snri. It was a pretty significant event then - his manic episode - no sleep for several days and started to break things around the house. Also very loud and constantly saying I’m ready to go down to the beach. Luckily for us he is not a big guy and not violent.. but still. No sleep - no one improves if there is no sleep. So, with the medication the hospital rx’d I was just ready to put out that big fire.. We have worked with two different psychiatrists since then for medication management. The first one was reluctant to be convinced of bipolar. His goal for us was just to be on lithium and lorazepam on as needed basis. So we started lowering to remove the olan. and snri. But as we chipped away at dose of olanzapine the hypomania was still there. So we suspected snri, but lowering that, the anxiety was back. We probably went too much too soon. We changed psychiatrists - one who did a thorough history and listening, actually listened to me read my journal entries. She could see hypomanic cycles. She too wanted goal of just lithium. But without very small dose of olanzapine the hypomanic/restlessness would cycle back. It’s taken time to see the pattern. That general pattern was mostly consistent for 5 yrs until February- when he had his first full manic episode in 5 yrs. He’s been on low doses of everything. I just read a report from Dr Joshua Smith’s recent research out of Vanderbilt (my hometown -Nashville) - although not about bipolar it’s about “hyperactive catatonia” - seems like an oxymoron to me but his research is antipsychotics can exacerbate it and treatments like clonazepam work. So it got me thinking…..I would love for just lithium as mood stabilizer maybe micro dose clonazepam and olanzapine as needed
      ~Tanya

      Delete
    5. Tanya, there are big overlaps between the biology of autism and bipolar, so it is not surprising that some people will be affected by symptoms of both.

      I find it interesting that you can improve symptoms of autism by targeting inflammation (auto-immune dysfunction). Not surprisingly it appears that you can improve symptoms of bipolar by targeting inflammation.

      I looked up a couple of my favourites and saw what effect they have on bipolar. While Ponstan seems not to be compatible with lithium, pioglitazone looks interesting.

      In the study below they were looking at depressive episodes rather than hypomania, but I think it is worth mentioning to your psychiatrist.

      Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial
      https://pubmed.ncbi.nlm.nih.gov/25620378/#:~:text=Conclusion%3A%20This%20study%20showed%20that,2%20diabetes%20or%20metabolic%20syndrome

      If your psychiatrist supports your trial of low dose clonazepam, that is great. A good dose to start with is 0.0006 mg/kg. If your son weighs 75kg that would give 0.045 mg. After 3 days you should be able to judge the effect.

      Note that calcium channel blockers may help with bipolar symptoms, Verapamil is one quoted example. We have seen in this blog that some people with autism benefit from blocking L type calcium channels (Verapamil, Amlodipine etc).

      Delete
    6. Excellent ideas thank you so much.. also maybe going back to the drawing board with folate/folinic trial as lithium add-on - it can modulate the inflammatory pathway. Peter your blog is a life-line

      Delete
    7. Peter I do want to mention we did try verapamil I think starting in 2016-2017. Also the pioglitazone had to look up - it’s called Actos here. We tried that when my son was younger when we were working with Bradstreet… but I will look in to it again.

      Delete
  14. Also I usually take cimetidine with my verapamil. There's multiple ways they can be synergistic. https://www.hindawi.com/journals/ijh/2020/9185361/

    ReplyDelete
  15. Peter,

    I tired searching the blog for this so I don't know if this exist. What do you know of vancomycin as an antiviral? Though this was interesting.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407158/

    -Stephen

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    Replies
    1. Stephen, that is interesting.

      Vancomycin is used by autism doctors and some people do respond. Is it the antibacterial effect or the antiviral effect? We can only wonder.

      Many antibiotics have potent secondary effects, often anti-inflammatory. Azithromycin is perhaps the best known example.

      Delete
    2. I guess vanco secondary effect is to decrease tnf-a.

      https://academic.oup.com/crohnscolitis360/article/1/2/otz015/5532749?login=false

      Delete
  16. Hi Peter,

    Have you written a post on csf fluid and autism? Bumetanide decreases csf fyi.

    https://www.healthline.com/health-news/spinal-fluid-may-be-connected-to-autism-risk#:~:text=Researchers%20said%20they%20found%20that,the%20case%20of%20a%20concussion.

    ReplyDelete
    Replies
    1. Bumetanide will reduce the volume of CSF (spinal fluid) just as it will reduce the volume of your blood. But, that assumes you do not compensate by drinking extra fluids. I think my son drinks twice as much water/fluids as me.

      It does appear that a problem with clearing waste products from the brain is a feature of some autism (and most age-related brain conditions).

      Your study is interesting and suggests elevated volume of CSF in autism.

      "The researchers found that extra cerebrospinal fluid was associated with lower nonverbal ability — or the ability to analyze and solve problems without using words.

      The study also showed that children with more cerebrospinal fluid had more problems sleeping. Researchers note the importance of this, because the circulation of this fluid, especially during sleep, is important to a healthy brain.

      This may help explain why children with autism often have sleep disorders, such as insomnia, and why poor sleep may worsen symptoms associated with autism."

      There can also be a problem with the recently discovered lymphatic system in the brain.

      https://sitn.hms.harvard.edu/flash/2016/how-a-newly-discovered-body-part-changes-our-understanding-of-the-brain-and-the-immune-system/

      We also have autophagy and mitophagy which can be impaired in autism and in older people.

      Delete
  17. Plus vancomycin increases fecal secretory iga.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833805/

    ReplyDelete
  18. I guess eating mushrooms increases secretory iga as well.

    https://pubmed.ncbi.nlm.nih.gov/22113068/

    ReplyDelete

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