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Involvement of Human Endogenous Retrovirus–H (HERV-H) in Autistic Spectrum Disorder
Human Endogenous Retroviruses (HERVs) constitute about 8–9% of the human genome, closely resemble infectious retroviruses and are considered to be remnants from ancient germ line viral infections, integrated as provirus in chromosomal DNA. During evolution HERVs were amplified and spread throughout the genome by repeated events of retrotransposition and/or reinfection and their integration can alter the structure and/or function of host genes. HERVs expression is implicated in many complex diseases that have multifactorial etiology and genetic basis, including type 1 diabetes, various types of tumors, autoimmune diseases, neuropathogenic diseases such as multiple sclerosis, schizophrenia and attention deficit hyperactivity disorder. In a previous study we demonstrated that peripheral blood mononuclear cells (PBMCs) of autistic patients (ASDs) showed high levels of HERV-H and had the potential to up-regulate HERV-H expression upon stimulation in culture, compared to healthy controls (HCs). HERV-H expression negatively correlated with the age of patients and high levels of HERV-H expression were associated to those with a severe impairment of developmental.
Objectives:
HERV-H expression in PBMCs has been assessed in larger samples of autistic children and in their parents to confirm our data and to evaluate the expression of HERV-H in the previous generation. The effect on HERV-H expression of substances able to modulate the expression of human retroviruses has been analysed. The possible link between HERV-H expression levels and clinical phenotype of the patients, in terms of age, levels of cognitive and adaptive functioning, severity of symptoms, environmental variables (such as parental exposure to toxic substances), recurrent infections and hormone treatments of mothers, has been evaluated.
Methods:
PBMCs from blood samples were stimulated in vitro and treated with different concentrations of Valproic acid (VPA) and non-nucleoside reverse transcriptase inhibitors, Nevirapine (NVP) and Efavirenz (EFV) for 72 hours. RNA from PBMCs was retro transcribed and amplified using primers specific for HERV-H, by real time PCR. A non-standardized questionnaire was administered to parents in order to identify associated risk factors.
Results:
A similar pattern of HERV-H expression, both basal and after stimulation in culture has been observed in ASDs and mothers. VPA treatment restores the HERV-H expression to basal levels in ASDs, induces an increase of the expression in mothers and has no effect in fathers. NEV and EFV decrease the expression levels of HERV-H, although at different concentrations in ASDs, mothers and fathers. Several risk factors related to maternal-fetus system (poliabortivity, hormonal treatment for infertility and history of infection) were highlighted.
Conclusions:
The high expression level of HERV-H in mothers suggests a maternal epigenetic transmission, able to confer an increased susceptibility to the disorder. Environmental factors, exposure to infections and drug treatments, can be considered trigger events that could modify the HERVs expression and the status of immune system in the mothers; modifications that could be in turn responsible of neurotoxicity and impaired synaptogenesis in the earliest stages of neuro-development in utero.