Does HIV Cognitive Impairment Tell Us Anything About Autism?

The answer is likely.  Although the specifics will no doubt be different, if there is a subset of persistent CNS viral infection related autism (as suggested by Persico and others), then the mechanism of impairment may be similar.

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The net effect is still that TNF alpha is elevated and with that both direct and indirect harm to neurons will take place.  Keeping a lid on TNF and ultimately removing the virus is the target we need to try to shoot for in ASD in the viral-mediated subset.

But can we identify the subset of children affected this way?  I think that we can – without performing brain biopsies of course.

Reminding You of a 53 year old Woman Rescued from the TNF alpha Prison: and other published literature.

This is the most noteworthy case –report I think I have ever read. It is on a par, even more impressive than the case report on spironolactone case I reported a few years ago.

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So she received a specific anti-TNF therapy and made significant cognitive recovery.

I selected spironolactone because it was well documented to reduce TNF-alpha.  I knew about Chez’ findings.

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In addition the child gained 2 years of language on specific language testing.  So here are two separate drugs acting on TNF-alpha showing significant benefits for language and social issues in ASD. 

Let’s add one more study to this.

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Pioglitazone is a powerful inhibitor of NF kappa B and that means it reduces TNF alpha. Here is what it did for children with autism.

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With that I will let you work on these concepts.  Clearly TNF alpha is a serious issue for many children with ASD.

Linking TNF-alpha to Glutathione Deficiency and Various Brain Symptoms

I’ve had the pleasure to publish with Dr James onm some very important findings regarding the loss of protection from both toxins and oxidative stress in fairly large cohort of children with autism.  The findings, apart from the genetics data more typical of autism, would likely be the same for ALL neurological chronic illnesses including schizophrenia, Parkinsonism, Alzheimer’s and other conditions.  ALL of these have been associated with low glutathione levels in the brain. I will explain why this is so important.  

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Recall Dr Chez’ very important data and observations that even after intervention with anti-inflammatory medications (IVIG, Steroids etc) children with ASD had elevated spinal fluid TNF-alpha (the master inflammatory regulatory messenger of the immune system).  He compared CSF TNF-alpha to blood.  It should always be less than 1.0(CSF/Blood) and as you can see it never was.

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Study this and tonight I will finish the discussion.  Right now I have to catch a plane to lecture in South Carolina. 

More Evidence TNF-alpha Allows Viral Persistence

This comment came on one of my think tank blogs from researcher and professor Dick Deth:

“Viruses such as XMRV are suppressed by methylation, and the enzyme methionine synthase is a master controller of methylation. We observed very powerful and rapid inhibition of methionine synthase (MS) transcription by TNF-alpha (>90% decrease of  MS mRNA). An examination of the promoter region of methionine synthase revealed a consensus site for NF-kappa-B binding which overlaps the normally promotional AP-1 site. Thus we can hypothesize that TNF-alpha decreases methylation activity via NF-kappa-B. This decrease will augment viral persistence and replication. Notably, MS is very sensitive to oxidative stress, implying that oxidative stress, initiated by any number of provocations, would increase susceptibility to viral infection. Persistent viral infection could in turn prolong/delay recovery from oxidative stress, leading to a persistent oxidative stress and persistent v (a self-reinforcing relationship). In other words we normally recover from an oxidative stress-producing event, but the presence of a viral infection can turn this into a chronic condition…”

This is exactly what we are observing in numerous conditions including XMRV, Autism and ME/CFS.  The good news is these conditions can be treated. 

Why I Am More Hopeful Now Than Ever About Autism, ME/CFS, HIV, Alzheimer’s and other Chronic Illnesses: the Stem Cell, TNF-alpha, Viral/Pathogen connection.

On this blog I have been writing about stem cells, hyperbaric oxygen (HBOT), and some incredible new observations related to reversing brain inflammation.  All of the diseases I listed above and a whole bunch more are tied to persistent inflammation.  Inflammation itself is very important to the body.  In a healthy person it doesn’t persist. It comes in response injury or infection – cleans that up – then stem cells communicate the need to stop the inflammation and heal.  To that extent, these chronic – persistent inflammatory conditions are the result of a failure of stem cells to do their job to counter inflammation. I will explain what is keeping them out of the process below and in future posts.

As this following picture demonstrates, the balance of inflammation regulation in the brain is complicated, intricate and precarious. But science has reached a point where we understand a large portion of the regulatory pathways.

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[Frontiers in Bioscience 14, 5291-5338, June 1, 2009]

Caption: Microglia are the primary recipients of peripheral inflammatory signals as they reach the brain. Activated microglia initiate an inflammatory cascade by releasing cytokines, chemokines, prostaglandins and reactive nitrogen and oxygen species (RNS and ROS, respectively). Bi-directional exchanges between microglia and astroglia amplify inflammatory signals within the central nervous system (CNS). Cytokines including interleukin (IL)-1, IL-6, tumor necrosis (TNF)-alpha and interferon (IFN)-gamma induce indoleamine 2,3 dioxygenase (IDO), the enzyme responsible for degrading tryptophan, the primary precursor of serotonin (5-HT), into kynurenine, which is eventually metabolized into quinolinic acid (QUIN), a potent NMDA agonist and stimulator of glutamate (Glu) release. Multiple astrocytic functions are compromised due to the excessive exposure to cytokines, prostaglandins, QUIN and RNS/ROS, ultimately leading to downregulation of glutamate transporters, impaired glutamate reuptake, excessive glutamate release and compromised synthesis and release of neurotrophic factors. Oligodendroglia suffer damage due to toxic overexposure to cytokines such as TNF-alpha, and diminished neurotrophic support, both of which promote apoptosis and demyelination. Copious amounts of glutamate are released from astrocytes in the vicinity of extrasynaptic NMDA receptors, whose activation leads to inhibition of BDNF synthesis. Excessive NMDA activation, caused by QUIN and D-serine, is compounded by diminished glutamate reuptake by astrocytes and oligodendroglia. NMDA-mediated excitotoxicity, combined with a consequent decline in neurotrophic support, and an increase in oxidative stress, synergistically disrupts neural plasticity and induces apoptosis (cell death).

So it doesn’t matter if we are talking about autism, post-stroke inflammation, Alzheimer’s, HIV dementia; the central mechanism is largely the same.

Now this is important to understand: if we have persistent inflammation in the brain, what is driving that signal? The immune system has lots of regulatory steps designed to keep it in balance, but despite all the intrinsic safeguards in the system – it has lost control. Why?

Some perspective: About 5 years ago I was sitting on a bus with Professor Thayne Sweeten. We were on our way to dinner to relax after a full day of brainstorming as a group of researchers interested in autism. Thayne is a bright guy. His PhD dissertation was Immune Activation and Autoimmunity in Autism. He explained from everything he had seen regarding the immune system of autism; the CSF observations, the increase in neopterin, etc,, that at least a significant subgroup of children had the immunological footprint of a persistent viral pathogen.

I agreed – and I still do agree – especially after 5 years of discoveries. And it doesn’t have to be a virus: many other pathogenic bacteria and fungi could cause the same response. But for simplicity let’s just say virus.

We don’t have to agree about which virus is persistent in autism, it actually doesn’t matter that much. I am surprised to hear myself say that, but after what I have learned in the last few months, I don’t think the actual virus is that important.  That is because most do not have a specific anti-viral drug (apart from HIV and some Herpes viruses).  Even in those cases the drugs are inadequate and something else is needed.

THE IMMUNE SYSTEM IS BLINDED

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The picture depicts the blind miraculously being given sight. I would love to see a miracle of immune unblinding in autism, or any of these other disorders.  Absent that we need to give it sight medically.

If you read my blog about this last night I spoke about the problem.  We have a raging immune response just like we would expect with a viral infection, except it doesn’t go away. Why?  The immune cells (particularly macrophages) seem to be blind and cannot find the enemy they are looking for.  So while they stumble around, unable to find the viral enemies, the entire system stays turned on.  And it will stay turned on until either stem cells say enoughits time to heal, or until the virus is eliminated.

The evidence is we don’t generate enough stem cell response to regulate this type of immune response – presumably because the viruses are still present.  Therefore, extra stem cells may help cool the immune fires. BUT, and it is an important but, do we want to down-regulate the immune system if a virus is still present? My belief is – no.

What we want is to make the virus go away and with that have the immune response naturally calm down.

To do that we have to give sight to the blind and help the macrophages find their targets.

To do this we are working with some of the finest biotech labs in Europe and we believe we have the solution.  More on that to come.

A brief but helpful discussion about TNF alpha is on wikipedia.  http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha

Mysterious Autism Virus(es) revealed?

So back to our immunologist.  Based on your years of training and experiences, you (like any good immunologist) suspect viruses may be behind chronic inflammation in the brain.  There are good reasons for that. Trolling through the index medicus at the national library of medicine (electronically – sadly I have never been there) turns up a huge number of hits connecting viral persistence to brain inflammation.

If we accept many if not most autism cases involve some form of CNS immune activation or inflammation, we should look for candidate viruses. So you may be thinking its time to consult a medical virologist.  Not a bad idea. Let’s do that.

I can go back to my colleague, Professor Persico.  He went a long way to define our understanding of inflammation in the brain; now we are calling on him to help us find our mystery virus or viruses.  Take some time and read the abstract below.

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Okay – let’s add BK virus, JC virus and SV40 (all polyomaviruses) to our list of possible mystery viruses. (Note: BK and JC are the names of the viruses, and SV40 is a byproduct of contaminated polio vaccine). Equally important it looks like we can scratch off CMV, EBV, HHV6, HSV1 and HSV2.  Any of these, could – in an isolated case – be actively involved in autism, but none seem to be commonly associated. I know some doctors have strongly advocated for HHV6 in autism. I realize they recommend treating the proposed HHV6 infection chronically with acyclovir or valcyclovir, so let me take a short diversion to address this.

Valcyclovir is a prodrug.  In the liver it converts to acyclovir.  The drug works by competing with natural thymidine kinase (an enzyme involved in DNA synthesis).  Here we need to go back to basic herpes virology. HHV6 does NOT express thymidine kinase. Therefore, it is IMPOSSIBLE for acyclovir or its prodrug to treat it.  So, regardless of what you think about the role of HHV6 in autism or chronic fatigue syndrome, these medications have NO PLACE in the treatment of these conditions. (ref. Sherris Medical Microbiology, Fifth Edition, McGraw-Hill Companies, 2010.)

Ok, I’ll get off my soapbox.  Back to our quest.

Let’s turn our attention to the possibility of a newcomer (at least newly discovered virus), xenotropic murine leukemia virus-related virus (XMRV retrovirus): a gammaretrovirus discovered by laboratories led by Joseph DeRisi at the University of California, San Francisco, and Robert Silverman and Eric Klein of the Cleveland Clinic. Some have recently suggested changing its name to Human Gamma Retrovirus.

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XMRV virus in isolated culture.

This is a somewhat like its second cousin HIV.  It is a retrovirus – meaning it can convert itself to DNA.  It is controversial, but it seems to be associated with some cases of chronic fatigue syndrome.

Before I go over the literature on this, I want to let you know I do check for the presence of XMRV virus and antibodies to it in a subset of children with autism.  It is occasionally positive.  Whether it is causing the autism symptoms or not is unknown. It is however difficult to ignore when it is positive.

Now for the evidence.  Two separate research teams – including Persico’s group – find NO association with XMRV and autism.  So apart from the few positive cases I have documented, little evidence supports XMRV in autism.  However, if it is present – it may be significant.

What other viruses should we consider? Prenatal viral infections (influenza, etc) seem to be potential problems.  They may even lead to persistence in the child (unlikely) or alteration of the immune responses in the child (more likely). These have not been found in post-mortem studies of children with autism, but they have been identified in the placenta.

Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway.

Neurosignals 2010;18(2):113-28. Epub 2010 Oct 2.

Parker-Athill EC, Tan J.

Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, University of South Florida, Tampa, Fla., USA.

Abstract

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have supported epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.

Is there anything left?  Despite the fact no one wants to talk about this, measles virus (MV) is a logical candidate virus. MV has a long history of infection, persistence and autoimmunity in the brain. But is there any evidence of its presence in the autism related brain?  The answer is yes, but the evidence is in dispute.

Not too long ago researchers pointed this out.

Autistic disorder and viral infections.

J Neurovirol. 2005 Feb;11(1):1-10.

Libbey JE, Sweeten TL, McMahon WM, Fujinami RS.

Department of Neurology, University of Utah, Salt Lake City, Utah 84132-2305, USA.

Abstract

Autistic disorder (autism) is a behaviorally defined developmental disorder with a wide range of behaviors. Although the etiology of autism is unknown, data suggest that autism results from multiple etiologies with both genetic and environmental contributions, which may explain the spectrum of behaviors seen in this disorder. One proposed etiology for autism is viral infection very early in development. The mechanism, by which viral infection may lead to autism, be it through direct infection of the central nervous system (CNS), through infection elsewhere in the body acting as a trigger for disease in the CNS, through alteration of the immune response of the mother or offspring, or through a combination of these, is not yet known. Animal models in which early viral infection results in behavioral changes later in life include the influenza virus model in pregnant mice and the Borna disease virus model in newborn Lewis rats. Many studies over the years have presented evidence both for and against the association of autism with various viral infections. The best association to date has been made between congenital rubella and autism; however, members of the herpes virus family may also have a role in autism. Recently, controversy has arisen as to the involvement of measles virus and/or the measles, mumps, rubella (MMR) vaccine in the development of autism. Biological assays lend support to the association between measles virus or MMR and autism whereas epidemiologic studies show no association between MMR and autism. Further research is needed to clarify both the mechanisms whereby viral infection early in development may lead to autism and the possible involvement of the MMR vaccine in the development of autism.

So what are we left with?

Possible: BK, JC, SV40 and infrequently but possibly XMRV.

From animal models: Borna Virus

Supported but controversial: Measles

Prenatal: Influenza, Rubella and others, but there is no evidence these prenatal viral exposures persist in the infant.

It is likely – as suggested by Persico’s team, that multiple viruses are simultaneously present and working together to cause this mischief we label autism.

NEXT UP: What can we do if these viruses are present?