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Introduction
Clinical findings in autism and relevance of dysfunctional calcium signalling in
:

    Brain Development
     Neurotransmitters
     Hormones
     Motor/Sensory Disturbances
     Blood Brain Barrier
     Epilepsy/Seizures
     Immunity and Inflammation
     Gastrointestinal Issues
     Membrane Metabolism
     Oxidative Stress
     Mitochondrial Dysfunction
     Gender Differences

Dysregulating Factors:
     Genetic Factors
     Hypoxia/Ischemia
     Toxins
     Infectious Agents
     Other

Conclusion

Links


Contact

HIV and Autism

Summary of abnormal biomedical findings in autism


 

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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T cell activation and human immunodeficiency virus replication after influenza immunization of infected children - Ramilo et al The Pediatric infectious disease journal 1996, vol. 15, no3, pp. 197-203 (25 ref.) Clin Biochem

Activation of virus replication after vaccination of HIV-1-infected individuals - Staprans SI et al J Exp Med. 1995 Dec 1;182(6):1727-37.

Transient increases in numbers of infectious cells in an HIV-infected chimpanzee following immune stimulation - Fultz PN et al AIDS Res Hum Retroviruses. 1992 Feb;8(2):313-7.

Human immunodeficiency virus-type 1 replication can be increased in peripheral blood of seropositive patients after influenza vaccination. O'Brien WA et al Blood. 1995 Aug 1;86(3):1082-9.

Measles/MMR vaccine for infants born to HIV-positive mothers [Intervention Protocol], B Unnikrishnan et al, The Cochrane Library 2009, Issue 1

Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1 - Stanley SK et al N Engl J Med. 1996 May 9;334(19):1222-30.

The efficiency of acute infection of CD4+ T cells is markedly enhanced in the setting of antigen-specific immune activation - Weissman D et al J Exp Med. 1996 Feb 1;183(2):687-92.

Antigenic stimulation by BCG vaccine as an in vivo driving force for SIV replication and dissemination - Cheynier Really et al. Nat Med. 1998 Apr;4(4):421-7.

Activation by malaria antigens renders mononuclear cells susceptible to HIV infection and re-activates replication of endogenous HIV in cells from HIV-infected adults - Froebel K et al Parasite Immunol. 2004 May;26(5):213-7.

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HIV's double strike at the brain: neuronal toxicity and compromised neurogenesis. Kaul Mum Front Biosci. 2008 Jan 1;13:2484-94

Viral myelitis: an update - Kincaid O, Lipton HL. Curr Neurol Neurosci Rep. 2006 Nov;6(6):469-74

Endogenous retroviruses in systemic response to stress signals. Cho K, Shock. 2008 Aug;30(2):105-16.

Human exogenous and endogenous retroviruses in autoimmunity. Christensen, T., book chapter - Recent research developments in immunology. Vol. 7 Editors: Pandalai, S. G.

Endogenous Retroviruses and Human Neuropsychiatric Disorders – Book Retrotransposition, Diversity and the Brain Robert H. Yolken et al

Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. Haughey NJ et al J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S55-61.

MCP-1 and CCR2 contribute to non-lymphocyte-mediated brain disease induced by Fr98 polytropic retrovirus infection in mice: role for astrocytes in retroviral neuropathogenesis. - Peterson KE et al J Virol. 2004 Jun;78(12):6449-58.

HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization. Norman JP et al, PLoS ONE. 008;3(11):e3731. Epub 2008 Nov 14.

Adsorptive endocytosis of HIV-1gp120 by blood-brain barrier is enhanced by lipopolysaccharide. Banks WA et al Exp Neurol. 1999 Mar;156(1):165-71.


See Infectious Agents for further references to mechanisms behind HIV-induced neurological dysfunction such as cellular and mitochondrial calcium overload in the brain (also present in ‘common’ autism)


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Early impairment of gut mucosal immunity in HIV-1-infected children. Quesnel A et al Clin Exp Immunol. 1994 Sep;97(3):380-5.

Poliovirus vaccine strains detected in stool specimens of immunodeficient children in South Africa. Pavlov DN Diagn Microbiol Infect Dis. 2006 Jan;54(1):23-30. Epub 2005 Nov 14.

Enteric pathogens associated with gastrointestinal dysfunction in children with HIV infection. Ramos-Soriano AG et al Mol Cell Probes. 1996 Apr;10(2):67-73.

Gastrointestinal dysfunction and disaccharide intolerance in children infected with human immunodeficiency virus. Yolken RH et al J Pediatr. 1991 Mar;118(3):359-63.

Intestinal malabsorption of HIV-infected children: relationship to diarrhoea, failure to thrive, enteric micro-organisms and immune impairment. The Italian Paediatric Intestinal/HIV Study Group. AIDS. 1993 Nov;7(11):1435-40.

Intestinal permeability in patients infected with the human immunodeficiency virus. Tepper RE Am J Gastroenterol. 1994 Jun;89(6):878-82.Efficacy of oral pancreatic enzyme therapy for the treatment of fat malabsorption in HIV-infected patients. Carroccio A et al Aliment Pharmacol Ther. 2001 Oct;15(10):1619-25.

The effect of antenatal vitamin A and beta-carotene supplementation on gut integrity of infants of HIV-infected South African women. Filteau S et al J Pediatr Gastroenterol Nutr. 2001 Apr;32(4):464-70.

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Effect of enzyme therapy on HIV-RNA and CD4 counts in HIV seropositive subjects with CD4 count 200 to 500 - Lange M et al Int Conf AIDS. 1996 Jul 7-12; 11: 91 (abstract no. We.B.3198). t. Luke's-Roosevelt Hospital, New York, NY, USA

HIV antiviral effects of hyperbaric oxygen therapy – Reillo MR et al, J Assoc Nurses AIDS Care. 1996 Jan-Feb;7(1):43-5

Disintegration of retroviruses by chelating agents - V. Wunderlich1 and G. Sydow1(1) April 1982. Central Institute for Cancer Research, Robert-Rössle-Institute, Academy of Sciences of the German Democratic Republic, Berlin, German Democratic Republic

Metal chelators as potential antiviral agents. Hutchinson DW. Antiviral Res. 1985 Aug;5(4):193-205 Klin Wochenschr. 1991 Oct 2;69(15):722-4.

Alpha-lipoic acid inhibits HIV replication - Grieb G. Med Monatsschr Pharm. 1992 Aug;15(8):243-4.

NAC, glutamine, and alpha lipoic acid. Interview by John S. James.Lands L, AIDS Treat News. 1997 Apr 4;(No 268):2-7.

Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Baur A et al Klin Wochenschr. 1991 Oct 2;69(15):722-4.

Lipids and retroviruses - Raulin J, Lipids. 2000 Feb;35(2):123-30.

Inhibition of Tat-mediated HIV-1-LTR transactivation and virus replication by sulfhydryl compounds with chelating properties - DEMIRHAN Ilhan et al. Anticancer Res. 2000 Jul-Aug;20(4):2513-7

Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection. Jariwalla RJ et al J Altern Complement Med. 2008 Mar;14(2):139-46.

Advances in two-metal chelation inhibitors of HIV integrase Authors: Johns, Brian A; Svolto, Angilique C Source: Expert Opinion on Therapeutic Patents, Volume 18, Number 11, November 2008 , pp. 1225-1237(13)

Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. Georgiou NA et al J Infect Dis. 2000 Feb;181(2):484-90.

Effect of desferrioxamine B, a metal chelating agent, on rhabdovirus multiplication.Conti C et al Boll Ist Sieroter Milan. 1990 Jun;69(2):431-6.

Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection. Martelius T Transplantation. 1999 Dec 15;68(11):1753-61.

Potent inhibitors of human immunodeficiency virus type 1 integrase: identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors. - Neamati N et al Mol Pharmacol. 1997 Dec;52(6):1041-55.

Thiamine disulfide as a potent inhibitor of human immunodeficiency virus (type-1) production - Shoji S et al, Biochem Biophys Res Commun. 1994 Nov 30;205(1):967-75.

The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation McMahon MA, et al J Biol Chem. 2008 Nov 14;283(46):31289-93. Epub 2008 Sep 24.

Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues Lisco A et al, Cell Host Microbe. 2008 Sep 11;4(3):260-70.

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. Baeten JM,et al J Infect Dis. 2008 Dec 15;198(12):1804-8.

Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. Zuckerman RA, et al J Infect Dis. 2007 Nov 15;196(10):1500-8. Epub 2007 Oct 31.

The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. Corey L et al J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):435-45.

Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. Schacker T, J Infect Dis. 2002 Dec 15;186(12):1718-25. Epub 2002 Nov 22.

Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a novel immune evasion mechanism. Fakioglu E, J Virol. 2008 Oct;82(19):9337-44. Epub 2008 Jul 30.

Inhibition of productive human immunodeficiency virus-1 infection by cobalamins - Weinberg JB, Blood. 1995 Aug 15;86(4):1281-7.

Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA into cellular DNA - Weinberg JB, Biochem Biophys Res Commun. 1998 May 19;246(2):393-7.

Methylation: a regulator of HIV-1 replication? - Yedavalli VR, Jeang KT. Retrovirology. 2007 Feb 2;4:9.

Epigenetic regulation of lentiviral transgene vectors in a large animal model - Hofmann A et al Mol Ther. 2006 Jan;13(1):59-66. Epub 2005 Sep 2.

Latent HIV-1 reactivation in transgenic mice requires cell cycle -dependent demethylation of CREB/ATF sites in the LTR - Tanaka J et al AIDS. 2003 Jan 24;17(2):167-75.

Methylation of cortical brain proteins from patients with HIV infection. Goggins Mum et al Acta Neurol Scand. 1999 Nov;100(5):326-31.

Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production. Mikovits JA et al Mol Cell Biol. 1998 Sep;18(9):5166-77.

Determinants of the establishment of human immunodeficiency virus type 1 latency - Duverger A et al, J Virol. 2009 Apr;83(7):3078-93. Epub 2009 Jan 14. 1 alpha,25-dihydroxyvitamin D3 inhibits productive infection of human monocytes by HIV-1 - Connor RI, Rigby WF. Biochem Biophys Res Commun. 1991 Apr 30;176(2):852-9.








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