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12 avril 2011 2 12 /04 /avril /2011 16:32

HIV infection in children - neurodevelopmental (autistic) outcomes and clinical pathologies - and their correlations to idiopathic autism

There is a striking correlation between neurodevelopmental symptoms found in children infected with HIV retrovirus and those children diagnosed with idiopathic Autism Spectrum Disorders (of still unknown aetiology). Furthermore, the underlying biomedical pathologies found in HIV-positive children are in many ways identical to biomedical pathologies found in children diagnosed with ‘common’ idiopathic autism.

The mechanisms of HIV-injury on host cellular systems have been identified in recent years and these pathologies often very closely match those found in autism, such as chronic microglial activation, mitochondrial disfunction, cellular calcium overload, oxidative stress, vasoconstriction (reduced blood flow to the brain), glutathione depletion, chronic inflammation of gastrointestinal and central and peripheral nervous systems etc (see list below).

Many treatment agents used in treating autism, whether with studied and proven beneficial effects or anecdotal reports of reducing autistic symptoms in some affected individuals, have antiretroviral mode of action and have been shown to inhibit the retroviral activity and/or reduce HIV viral load.


Neurodevelopmental findings in children infected with HIV retrovirus

Impairments in language, especially expressive language, behavioural symptoms: irritability, lack of social skills, repetitive actions (rocking etc).

Severity of autistic symptoms in HIV positive children is correlated to levels of retroviral load/replication, as well as CD4+ levels. Symptoms of autism – deficits in language, behaviour and social skills – in HIV infected children often recover upon administration of single or combination antiretroviral treatments, at least to some degree. Sometimes recovery is complete, with total remission of autistic symptoms.

HIV infected children sometimes develop normally and regress later, usually between 1.5-2 years of age. This is linked to increased HIV viral load.

Latent retrovirus can be reactivated by vaccinations. HIV viral load has been observed to sharply increase following adminstration of various vaccines (animal studies strongly support this observation). In addition to this, live virus vaccines, especially MMR, often come with a warning for HIV infected individuals with low CD4+ counts – inability to mount appropriate immune responses results in vaccine virus persistence. For example polio vaccine strain has been found in gastrointestinal tract of vaccinated individuals. No antibody production to Dtp or measles live virus vaccine. These findings have lead to proposals that both immunotherapy and vaccination of HIV-infected individuals should be accompanied by administration of an antiviral drug(s). In addition, it is suspected that exposure to antigenic stimulation through vaccinations may enhance the susceptibility of uninfected subjects to HIV-1 


Gastrointestinal findings in HIV positive children parallel gastrointestinal abnormalities found in idopathic autism:

Leaky gut and malabsorbtion of nutrients

Dysregulated production of digestive enzymes (impaired pancreatic function)

Abnormal immune reactions to gliadin and casein

Lactose intolerance

Sugar intolerance

Inability to digest complex carbohydrates

Inability to absorb fats and proteins

Gastrointestinal pathogen overload: secondary intestinal viruses, bacterial overload.

Abnormal immune reactivity to candida albicans.

Others:

Impaired fine and gross motor skills in HIV positive children

Impaired sensory – auditory and visual processing

Subclinical hypothyroidism (in adults, no data on children)



Pathological mechanisms in HIV infection

HIV retrovirus causes calcium overload and mitochondrial dysfunction (also found in idiopathic autism)

HIV causes oxidative stress and glutathione depletion (also found in autism)

HIV causes microglial activation and inflammation (also found in autism)

HIV combined with bacterial agents causes breakdown of the blood brain barrier (bbb breakdown suspected in autism)

HIV causes glutamate exitotoxicity (dyregulated GABA/glutamate mechanisms observed in autism)

HIV causes vasoconstriction - tightening of blood vessels that supply oxygen to brain (observed in autism)

HIV inhibits methylation (abnormal methylation found in autism)


Many modalities currently used for treating autism have proven or suspected antiretroviral effects:

• chelation of metals inhibits HIV virus integration into human DNA. Retroviruses in general are desintegrated by chelation agents in vitro. Several chelators have been patented as antiretroviral agents. Several agents with chelating properties, such as alpha lipoic acid (ALA) and NAC have been shown to reduce viral load in HIV positive individuals
• Tetracycline antibiotics (one currently on trial for autism) inhibit HIV in vitro through same mechanism as chelation agents.
• HIV is inhibited by glutathione and agents that raise glutathione
• Acyclovir/valacyclovir (antiviral agent with anti-herpevirus activity, with anecdotal reports of amelioration of autistic symptoms) has been shown to reduce HIV viral load in HIV positive individuals. The mechanisms are not clear. 
• Hyperbaric oxygen has been shown to inhibit HIV and reduce viral load.
• Pancreative enzymes trial showed beneficial effect in HIV positive.
• Methylation agents such as cobalamins and SAMe directly inhibit HIV activity and maintain its latency.

 

References


Correlation between computed tomographic brain scan abnormalities and neuropsychological function in children with symptomatic human immunodeficiency virus disease. Brouwers P et al Arch Neurol. 1995 Jan;52(1):39-44.

Early language development in children exposed to or infected with human immunodeficiency virus. Coplan J et al Pediatrics. 1998 Jul;102(1):e8.

Neurodevelopmental/neuroradiologic recovery of a child infected with HIV after treatment with combination antiretroviral therapy using the HIV-specific protease inhibitor ritonavir. Tepper VJ et al Pediatrics. 1998 Mar;101(3):E7.

Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team. Raskino C et al Pediatrics. 1999 Sep;104(3):e32.

Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. Pizzo PA et al N Engl J Med. 1988 Oct 6;319(14):889-96.

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children. Jeremy RJ et al Pediatrics. 2005 Feb;115(2):380-7.

Neurocognitive functioning in pediatric human immunodeficiency virus infection: effects of combined therapy. Shanbhag MC et al Arch Pediatr Adolesc Med. 2005 Jul;159(7):651-6

 

CD4+ helper T cell depression in autism. Yonk LJ et al Immunol Lett. 1990 Sep;25(4):341-5.

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