**5. The contribution of human endogenous retroviruses in disease development**

HERV expression is tightly controlled in normal adult tissues but is reported to be aberrantly expressed in cancer [68], inflammatory and autoimmune diseases [91], aging [92], type 1 diabetes [93] neurological disorders [94] and recently also viral disease [83, 95, 96]. Most of the diseases in which HERVs play a role as cofactor are characterized by a multifactorial aetiology and an inflammatory landscape. As such, HERVs have been proposed as spanning the bridge between environment and genetic background and as shapers of the immune system**.**

#### **5.1 Human endogenous retroviruses as shapers of the immune system**

HERVs can modulate the human immune response by different mechanism. In fact, being integrated as proviruses within the genome and physiologically expressed, HERV antigens can be recognized by the innate immune system as 'self-determinants' but also as potential pathogens. Probably due to their similarity with exogenous viral proteins they are able to activate pathogen recognition receptors (PRRs) by evoking the production of pro-inflammatory mediators (such as IFN, cytokines and chemokines), which in turn can activate and trigger the adaptive immune response [42]. Moreover, the involvement of HERVs in the host antiviral immune system seems to be linked to the Interferon pathway by acting as enhancer elements to directly affect the expression of adjacent interferon-stimulated genes [53, 54, 97]. Since HERVs are an integral part of host immunity, they protect the host from exogenous retroviral infections by PRRs, of which a major class are the Toll-like receptors (TLRs), the first line of defence in detecting a wide variety of pathogens. TLRs' engagements with viral components lead to the activation of MAP kinase and NF-kB resulting in the production of pro-inflammatory cytokines, involved in the infection control. It is also known that HERV RNAs are able to activate the immune system, thus stimulating the production of pro-inflammatory cytokines, which in turn can activate and prime the adaptive immune response [42]. This mechanism could be explained by the presence of transcriptional regulatory elements within retroviral long terminal repeats LTRs [98, 99]. This feedback loop made by HERV upregulation, inflammatory mediators and epigenetic dysregulation could be one way in which HERVs could have pathogenic potential leading to chronic stimulation of the immune system that could sustain the development and/or the progression of several human diseases.

#### **5.2 The role of human endogenous retroviruses in neuroinflammatory and neuropsychiatric disorders**

Outdated scientific evidence has reported the possibility of different viruses such as herpesviruses, HIV and Ebola virus to reach the central nervous system (CNS) contributing to the development of diseases. As such, despite the inaccessibility of CNS and the immunological structure that makes it a 'privileged district', the viral replication can occur by exceeding controls and can also happen multiple times during an individual's lifetime increasing the risk of developing neuropathologies [100]. In the last few decades, many researchers demonstrated that the activation of endogenous viral sequences in response to exogenous stimuli, especially viruses, can contribute to a variety of neuroinflammatory and neuropsychiatric disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), schizophrenia (SCZ) and bipolar disorder (BD). The pathways in which retroelements are involved in derailment of the nervous system are diverse: HERVs mainly interact with innate and adaptive immunity [52, 101], LINE activity is linked to neurogenesis, in particular neuronal differentiation and cognitive processes, both in adult brain and in progenitor cells [102, 103], and Alu elements, the most common member of SINEs, are involved in neurogenesis, brain development and cognition pathways [102, 104]. The first paper describing the involvement of HERVs in neurological disorders, especially in MS, dates back to the late 1900s when Perron and colleagues discovered retroviral elements in the leptomeningeal cells of MS patients [105]. From this initial work, several studies succeeded, both *in vitro* and *in vivo*, culminating in the identification of an aetiopathogenetic model in which HERV-W was further revealed to play functional roles in inflammatory processes. Specifically, pro-inflammatory cytokine expression was shown to be induced in both human and murine monocytes upon *in vitro* stimulation with HERV-W recombinant Env protein by a process that required TLR-4 receptor activation [69]. In line with these intriguingly findings, several research groups have contributed to the topic, focusing on different aspects concerning the role of HERVs of the aetiology and/or progression of the disease. MS is a neurodegenerative and neuroinflammatory disease affecting CNS in which it causes multifocal demyelinating lesions leading to physical and cognitive impairments and despite the plethora of studies, definitive proof regarding the aetiology being still lacking. In this setting, HERV-W Env protein has been extensively studied and to date has been recognized as a contributor factor in the MS pathogenesis. As such, the expression level of HERV-W in the brain of MS patients positively correlates with the severity of the clinical signs [106]. Moreover, the env transcripts and proteins of HERV-W are overexpressed in the brain [107] and in peripheral blood and serum of MS patients [108, 109] as a constant imprinting of the disease. Another important aspect characterizing the role of HERVs in MS is the interplay of HERVs with the immune system. Indeed, HERVs can stimulate both the production of proinflammatory mediators and innate and adaptive immune cells, which in turn could affect endothelial cells of the blood-brain barrier as well as oligodendroglial precursor and microglial cells [94]. Another pathological condition in which HERV activity has been investigated is ALS, a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS is also characterizing by an imbalance of the immunological mediators with a marked production of inflammatory cytokines. The first demonstration of the involvement of a HERV was the discovery of the activation of HERV-K (subtype HML-2) in the brains of individuals with ALS [110, 111]. Subsequently, the reverse transcriptase activity of

#### *Human Endogenous Retroviruses in Autism Spectrum Disorders: Recent Advances… DOI: http://dx.doi.org/10.5772/intechopen.108671*

HERV-K was identified in brain, cerebrospinal fluid (CSF) and blood of ALS patients [112, 113], and the expression of HML-2 Env transcripts and protein was found in cortical and anterior horn cells of the spinal cord samples [114]. Although there is consistent evidence linking HML-2 to ALS, very little is known about the mechanisms by which it may cause observed neurotoxicity. Recently, the neurotoxicity of HML-2 Env was clarified in transgenic animals that express the envelope protein developing an ALS-like syndrome. Interestingly, these observations provide the possibility to use HERV-K env-specific antibody in preclinical models to prevent Env toxicity and pave the way for new treatment strategies in sporadic ALS [115]. Schizophrenia, a major neuropsychiatric disorder, is a chronic brain disorder, and when active, symptoms include delusions, hallucinations, trouble with thinking and concentration and lack of motivation [5]. While disease onset typically occurs in late adolescence or early adulthood, several lines of evidence suggest that SCZ results from aberrations occurring in foetal development [116]. Furthermore, growing evidence demonstrates the increased risk of SCZ following early-life exposure to infectious agents or inflammatory stimuli, suggesting the involvement of the immune system in the aetiopathogenesis of the disease [117]. The strongest evidence for an association between HERV and SCZ comes from studies of HERV transcripts in the brain, cerebrospinal fluid and blood samples from affected individuals in which elevated levels of HERV-H, HERV-K and HERV-W were detected [72, 118, 119]. HERV-W Env protein expression in hippocampus was recently shown to alter the N-methyl-d-aspartate receptormediated synaptic organization and plasticity leading to defective glutamate synapse maturation, behavioural impairments and psychosis [120]. In addition, the epigenetic status of HERV-K sequences, particularly lower methylation levels in blood samples, has been indicated as marker of the early stages of SCZ [119]. Similarly, HERV-W transcripts and proteins were found to be elevated in the blood, CSF and brains of BD patients [118, 121, 122]. BD is a group of brain disorders that cause extreme fluctuation in a person's mood, energy and ability to function [5]. The precise aetiopathology of BD is unclear, and several reports indicate the involvement of the innate and adaptive immune system including inflammation [123]. Notably, an association between HERV-W Env protein, an increased level of IL-1β and an earlier disease onset was described in BD patients with respect to patients who were negative for HERV-W Env protein, suggesting HERV-W as marker able to define a specific group of patients in bipolar condition [122].
