Human endogenous retrovirus type W (HERV-W) in schizophrenia: A new avenue of research at the gene – environment interface
MARION LEBOYER 1,2,3,4 , RYAD TAMOUZA 5 , DOMINIQUE CHARRON 5 , RAPHA Ë L FAUCARD 7 & HERV É PERRON 6,7,8
1 AP-HP, Henri Mondor-Albert Chenevier Hospitals, Department of Psychiatry, Creteil, France, 2 INSERM, U 955, Psychiatry Genetic team, Creteil, France, 3 University Paris East, Faculty of Medicine, UMR-S 955, Creteil, France, 4 Fondation fondaMental, French National Science Foundation, Creteil, France, 5 Immunology and Histocompatibility Department and INSERM, U 940, Saint-Louis Hospital, Paris, France, 6 Ecole Doctorale BMIC, Universit é Claude Bernard, Lyon, France, 7 GeNeuro Innovation, Bioparc Lyon-La ë nnec, Lyon, France, and 8 GeNeuro, Plan-Les-Ouates, Geneva, Switzerland
Abstract Objectives. Provide a synthetic review of recent studies evidencing an association between human endogenous retrovirus-W (HERV-W) and schizophrenia. Methods. Bibliography analysis and contextual synthesis. Results. Epidemiological studies suggest that the aetiology of schizophrenia is complex and involves a complex interplay of genetic and environmental fac-tors such as infections. Eight percentof the human genome consists of human endogenous retroviruses (HERV), and this part of the genome was previously thought to be without importance, but new research has refuted this. HERVs share similarities with viruses and it is assumed that HERVs are present in the genome as a result of retroviruses infecting germ line cells many million years ago. A specifi c type of HERVs, called HERV-W, has through several recent studies been associated with schizophrenia. Elevated transcription of HERV-W elements has been documented, and antigens of HERV-W envelope and capsid proteins have been found in blood samples from patients. Viruses that have been implicated in pathol-ogy of schizophrenia, such as herpes and infl uenza, have been shown to activate HERV-W elements, and such activation has been associated with elevated biomarkers of systemic infl ammation. New research indicates that HERV-W may be an important genetic factor interplaying with the environmental risk factor of infections and that, through this, HERV-W may be important for disease pathogenesis. Conclusions. A lifelong scenario of a detrimental interaction between infectious agents and HERV-W genes may decipher the actual development and course of schizophrenia. Further research is needed to fi nd out if specifi c treatment strategies could reduce the expression of HERV-W and if this will be associated with remission.
Schizophrenia is a severe psychiatric disorder with a complex genetic background interacting with environmental factors (van Os and Murray 2008). Epidemiological data, post-mortem analyses, as well as brain imaging studies have shown that schizophre-nia is likely to begin with neurodevelopmental impairments occurring early in life. In this respect, the identifi cation of environmental factors that might trigger alterations of brain neurodevelopment offers promising tools for unravelling the aetiology of schizophrenia, for developing innovative thera-peutic approaches and even for envisaging preventive
intervention. Among them the place of birth, in particular urban environment (Eaton et al. 2000), its seasonality in the winter – spring period (Torrey et al. 1997), maternal infections during pregnancy caused by, e.g., rubella (Brown et al. 2001), infl uenza virus (Brown et al. 2004), herpes simplex virus type 1 or 2 (Buka et al. 2001), or Toxoplasma gondii (Mortensen et al. 2007) and immunological disturbances with elevated pro-infl ammatory cytokines (Ashdown et al. 2006) are associated with an increased risk for schizophrenia. This association of perinatal infec-tions with schizophrenia has recently been reviewed (Brown and Derkits 2010). However, other studies
the genome of healthy humans from different ethni-cal origins (Mirsattari et al. 2001). Interestingly, these genetic elements retain characteristics of retro-viruses while generally representing multicopy gene families with both Mendelian and non-Mendelian genetic features.
Unlike other viruses, which genome normally remains separated from host ’ s cell genome, retrovi-ruses have the ability to insert their genomic copy within host ’ s chromosomes and to further express their genes from such integrated copies in cellular DNA. Specifi c enzymes are encoded by retroviruses, carried along with retroviral RNA genome in viral particles, permit the reverse transcription of RNA into DNA with appropriate “ sticky ” extremities and, fi nally, its integration into chromosomal DNA of infected cells (Figure 1). Nonetheless, classical infec-tious (exogenous) retroviruses such as human immu-nodefi ciency virus (HIV) may insert provirus copies into host ’ s genome, but exclusively into cells express-ing specifi c surface receptor(s) allowing viral pene-tration (Borchers and Tomer 1999; Mack et al. 2000). Exogenous retroviruses are present in a restricted number of cells and cannot be genetically transmitted to progeny by the genetic route.
Endogenous retroviruses that are present in humans are assumed to have entered the mamma-lian genome species several million years ago, after infection of a germ cell and a subsequent integration of a provirus in chromosomal DNA. When this provirus introduction did not impair the gamete fusion and could give birth to a viable newborn with reproductive potential, unlike exogenous retrovi-ruses, it resulted in the presence of one or more genetically inherited retroviral copy(ies) in every cell of the progeny. They thereby created a modifi ed genome that could further be transmitted and modifi ed with species evolution, as illustrated for HERV-W elements in Figure 2. In addition such “ germ-line retroviral integrations ” have repeatedly occurred during evolution and could also dissemi-nate within genomes with properties of “ mobile genetic elements ” together with various recombina-tion events (Pavlicek et al. 2002). In fact, HERVs are part of the Superfamily of transposable elements (transposons, retrotransposons, and endogenous ret-roviruses) representing about 42% of the human genome. HERVs (8% of human DNA) constitute the most evolved members of these mobile genetic elements (Griffi ths 2001). They have probably played a role in the molecular genetics phenomena responsible for intra- and inter-species gene trans-mission, as well as intracellular gene transposition and recombination, underlying the evolution of spe-cies known to result mostly from genetic modifi ca-tions providing selective advantage to environmental
have also provided evidence that certain infections later in life, during childhood and adulthood, might constitute additional/secondary risk factors associ-ated with schizophrenia (Dickerson et al. 2006). Pre-natal infection and anti-viral like infl ammatory responses in animal models have also revealed neu-rophysiological, neurocognitive and behavioural abnormalities likely to be induced by certain cytok-ines and consistent with those observed in schizo-phrenia (Nawa and Takei 2006; Boksa 2010; Meyer and Feldon 2010). This was recently confi rmed in monkeys infected with Infl uenza virus during preg-nancy with offspring presenting schizophrenia-like neurobehavioral and MRI abnormalities with high prevalence after 1 year of age (Short et al. 2010).
At the genetic level, the contribution of the immune-related diversity, namely immunogenetics, was recently highlighted in studies involving large cohorts of patients and showing associations between common alleles of the major histocompatibility complex (MHC) and schizophrenia (Shi et al. 2009; Stefansson et al. 2009). This revealed consistent with a re-analysis of Genome Wide Associations revealing that loci implicated in infl ammation and immune pathways are involved in schizophrenia development (Jia et al. 2010). Nonetheless, suscep-tible genotypes would rather be involved in the con-trol of infl ammatory immune responses than in the initiation and/or the progression of the disease.
Thus, despite these converging fi ndings, the mech-anisms responsible for the increased schizophrenia risk in offspring exposed to these environmental fac-tors, the nature of their interaction with “ suscepti-ble ” genotypes, and the possible links between those factors and the mechanisms underlying the remit-ting/relapsing evolution of schizophrenia remain to be fully understood.
The present review describes how Human Endogenous Retroviruses belonging to the “ W ” family (HERV-Ws) could potentially constitute a bridge between the aetiopathogeny and the lifelong history of the disorder, at least in patients with neu-rotoxicity, infl ammation and severe cognitive defi -cits. We thus propose a new hypothesis federating the contribution of major genetic and environmental factors in schizophrenia mediated by a pathogenic impact of HERV-Ws.
Human Endogenous Retroviruses
Human endogenous retroviruses (HERV) are components of the genome that can be transmitted to subsequent generations through gametes, but have evolved differently from “ structural genes ” , as e.g., they do not have the same copy number within
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Figure 1. Genomic structure, virionic representation and replication cycle of a retrovirus. (A) Infectious retroviruses are composed of gag, pol, and env genes, fl anked by two long terminal repeats (LTR) and a primer-binding site. (B) Gag represents structural proteins, env envelope proteins and pol retroviral enzymes. These enzymes are notably involved in specifi c retroviral features such as reverse-trancription of RNA into DNA with further integration of a genomic copy (Provirus) into host ' s cell chromosomal DNA. (C) General representation of a complete retroviral replicative cycle with central step of proviral copy integration into host ' s cell DNA. (Adapted from: C. Bernard “ Prot é ines du r é trovirus endog è ne MSRV/HERV-W: é tude des propri é t é s physiopathologiques et applications en immunoth é rapie ” , PhD Thesis, University of Lyon-1, France, 2009.)
infl uence (Challem and Taylor 1998). As a result, HERVs can behave as “ genetic viruses ” and, when not mutated or disrupted by recombination, become expressed when activated by specifi c triggering fac-tors. Thus, even if now greatly altered by many inac-tivating mutations or deletions, their responsiveness to environmental infl uences is an intrinsic property. It naturally places HERV elements at the frontline of gene – environment interactions that characterizes complex diseases such as schizophrenia (Perron and Lang 2010).
During the nineties, the discovery of retroviral particles associated with functional reverse-transcriptase (RT) activity, expressed in cells from patients with multiple sclerosis (Perron et al. 1991), has led to the discovery of a novel HERV element, named “ multiple sclerosis associated retroviral ele-ment ” , MSRV (Perron et al. 1997) and further led to unravel the yet ignored family HERV-W, to which MSRV belongs (Blond et al. 1999). The involve-ment of HERV-W and, more particularly, of its virion-producing MSRV element in Multiple Scle-rosis (MS) has been evidenced and confi rmed by epidemiological and biological studies, as recently reviewed (Perron et al. 2009). The resulting produc-tion of HERV-W/MSRV Envelope (Env) protein has later been shown to induce potent activation of innate immunity and subsequent release of pro-infl ammatory cytokines. This involves Toll-like receptor (TLR-4) initial agonist effect (Rolland et al.
2006) and, eventually, a secondary “ superantigen-like ” effect induced by polyclonal activation of T lymphocytes (Perron et al. 2001).
Human endogenous retroviruses W and schizophrenia
The fi rst study linking an HERV and schizophrenia showed that MSRV (HERV-W) sequences were differentially represented in the genome of a schizo-phrenic patient compared to its non-affected monozygotic twin (Deb-Rinker et al. 1999). Several independent studies, which analyzed post-mortem cerebral RNA or specifi c RNA in CSF and circulat-ing blood, have confi rmed this peculiar HERV-W expression in certain patients with schizophrenia (Yolken et al. 2000; Karlsson et al. 2001, 2004; Yao et al. 2008). Most importantly, when other HERV families were tested in parallel, only HERV-W showed signifi cant expression in schizophrenia (Yolken et al. 2000). Our study evidencing two major HERV-W antigens, envelope (Env) and matrix/capsid poly-protein (Gag), concomitantly present in the serum of about one-half of a schizo-phrenic patient study group, has confi rmed this association. It has also evidenced that such antige-naemia is concomitant with elevated serum level of C-reactive protein (CRP, a systemic infl ammation biomarker) without any coincident infectious/infl ammatory event (Perron et al. 2008). Schizophrenic
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HERV-W and schizophrenia 83
Figure 2. Endogenous evolution of ERV-W Family from Primates to Humans (HERV-W). The schematic representation of the entry of Endogenous retroviral type W progeny in the germ line of superior primates, after initial infection by an exogenous member, illustrates corresponding genome studies (Voisset et al. 1999). Genetic transmission and dissemination during evolution has generated the multicopy HERV-W family of endogenous elements now present in the human genome (Blond et al. 1999).
patients with elevated CRP seem to be those devel-oping cognitive decline (Dickerson et al. 2007). Thus, the presence of this HERV-W Env protein with potent pro-infl ammatory properties (Perron et al. 2001; Rolland et al. 2006) correlating with CRP levels suggests that it could “ fuel ” such sub-acute chronic and systemic infl ammation. In brain, HERV-W RNA expression was found specifi cally elevated in cortical tissue from patients with schizo-phrenia (Yolken et al. 2000), thus indicating intra-cerebral HERV-W “ local ” involvement superimposed to the systemic presence of HERV-W related pro-teins and RNAs in these patients (Karlsson et al. 2004; Perron et al. 2008).
As neurotoxicity can be mediated by several pro-infl ammatory cytokines from the innate immunity pathway (Chao et al. 1995) their systemic and brain-targeted activation by HERV-W Env appears to be relevant in this pathogenic context. In particular, Tumour Necrosis Factor alpha (TNF- α ) reveals cen-tral as a pro-infl ammatory cytokine since shown to provide positive feed-back signalling on HERV-W expression (Serra et al. 2003) and, together with its main receptor TNF-R1, to be elevated in schizophre-nia (Hope et al. 2009). TNF- α may thus play a crit-ical role in infl ammatory neurotoxicity. TNF-R1 has been repeatedly identifi ed among genes of susceptibil-ity to MS (De Jager et al. 2009; Kumpfel and Hohlfeld 2009; Swaminathan et al. 2010). This should be worth being specifi cally investigated in the sub-group of patients with schizophrenia and elevated CRP.
A recent study has also provided major evidences in favour of a direct effect of HERV-W Env protein on key neuromediators and genes associated with schizophrenia: over-expression of HERV-W env gene in transfected human glioma cells up-regulated brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 (Huang et al. 2010). This also increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein, necessary for BDNF expres-sion. Thus, HERV-W Env protein triggered BDNF production through an activation of its promoter. In addition to these highly relevant observations sup-porting a direct involvement of HERV-W Env in disease-associated neuronal dysfunctions, the same study once more confi rmed the signifi cant detection of HERV-W Env mRNAs and of retroviral reverse transcriptase activity in blood from 42 of 118 Chinese patients with recent-onset schizophrenia, but not in the 106 controls (Huang et al. 2010). This study replicates, in a genetically distinct population-group, the notion that a sub-group of schizophrenic patients is associated with HERV-W abnormal expression.
Role of environmental factors: examples of infectious agents inducing epigenetic activation of HERV-W elements
Various viruses and other infectious agents have been viewed as potential causative factors of schizophrenia
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84 M. Leboyer et al.
Figure 3. Scenario for a pathogenic cascade involving HERV-W in schizophrenia. An infectious or major infl ammatory event during pregnancy, such as Infl uenza virus or Toxoplasma gondii infections, can trigger HERV-W elements activation in embryo. Subsequent DNA modifi cations would cause aberrant HERV-W Env expression and might lead to an abnormal neurodevelopment, in a general context of infl ammatory neurotoxicity. Particular stress conditions and/or a secondary postnatal infection with neurotropic agents such as, e.g., cytomegalovirus (CMV) or herpes simplex virus type 1 (HSV-1) would reactivate latent and/or in-utero modifi ed HERV-W elements. This would result in Env-induced toxicity focused in brain and leading to the symptomatic onset of schizophrenia.
onset and development and it has long been thought that the aetiology of the disease could fi t to a “ simple infectious cause ” , as infectiology had classically evi-denced causes of many diseases over the 20th cen-tury. Today, it becomes obvious that schizophrenic disease is not directly caused by infections, in which microbial replication and propagation are directly involved in the pathogeny. “ Re-positioning ” neo-natal and later infectious events in interplay with endogenous retroviral elements now makes it pos-sible to describe a new avenue of research federating lifelong links between (i) genetics, involving HERV elements, (ii) environmental factors represented by infectious agents and (iii) the natural history of schizophrenia.
Indeed, HERV elements are usually not expressed, because consisting mostly in defective or inactive copies. Epigenetic silencing mechanisms such as DNA methylation of gene promoter regions are also preventing their expression (Schulz et al. 2006). This explains why latency is the rule in such poten-tially active HERV copies. However, in the case of HERV-W family, it is now well understood that certain viral agents and transactivators can trigger the reactivation of HERV-W copies, potentially functional but normally latent within the human genome (Perron and Lang 2010). In a pathogenic context, reactivation of such elements results in the production of an envelope protein (HERV-W Env) eventually associated with retroviral particles (MSRV), which strongly stimulates an immune
pro-infl ammatory cascade through TLR4 receptor pathway and initiates neurotoxic effects (Chao et al. 1995; Menard et al. 1997; Rolland et al. 2006). TNF- α could be of particular relevance since pro-viding a feed-back amplifi cation loop of HERV-W expression (Serra et al. 2003) as previously dis-cussed, but also as further exposed with the role of Herpesvirdae since TNF- α exerts a critical control on Herpesvirus infections (Vilela et al. 2010).
Thus, upstream this pathogenic cascade, certain environmental viruses that have been associated with schizophrenia can be co-factors in the activation of HERV-W elements primarily in the embryonic period with potential modifi cations creating a “ HERV genetic risk ” in face of, in the young adult period, secondary infections with neurotropic viruses intruding in the brain (Figure 3).
In most instances, neurotropic viruses do not cause major infections but may intrude into the brain where they can be blocked by perivascular macrophages or microgliocytes with strong innate immune defence, avoiding major infl ammatory response as induced by lymphocytes when the adap-tive immunity is engaged. Unlike in other organs and tissues, lymphocytes are normally absent from the brain and exert a distant or discrete survey, which represents the “ Brain immune privilege ” (Pachter et al. 2003) preserving nervous tissue from major immune reaction resulting in highly detrimental tis-sue scars. If eliminated, viruses like Herpesviridae may still express “ early gene products ” capable to
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HERV-W and schizophrenia 85
Herpesviridae
Herpesviridae comprise viruses shown to be associ-ated with increased risk of psychosis in offspring of mothers infected by Herpes Virus type 2 (Buka et al. 2008), as also reviewed by Brown and Derkits (2010). They also comprise viruses shown to be associated with disease in adult life (Dickerson et al. 2003, 2006). Several independent studies have shown that they can act as environmental co-factors triggering reactivation of HERV-W copies in the human genome. For example, infection by herpes simplex type 1 (HSV-1), or transfection with its “ immediate-early ” (IE) transactivating genes, stimu-lates MSRV particles expression in leptomeningeal cells from patients with multiple sclerosis (MS) but not in those from non-MS patients, apparently devoid of such HERV-W genetic potential (Perron et al. 1993). It illustrates the transactivation capacity of Herpesviridae on HERV-W elements, but also the need of a peculiar HERV-W copy in the genome of infected cells for the pathogenic expression of virions or HERV-W Env protein. This transactivating effect of Herpesviridae, which can also be effi cient on methylated promoters (Bhende et al. 2004), was confi rmed in series of studies recently synthesized in a review devoted to epigenetic of complex infl amma-tory diseases (Perron and Lang 2010). Thus, the signifi cant association with schizophrenia, but never with MS, reported for another member of Herpes-viridae family, i.e., the “ grey matter-tropic ” Cytomegalovirus (CMV; Dickerson et al. 2006), appears very sensible as one would expect that such viral triggers would reactivate pathogenic HERV-W expression in tissues where lesions or dysfunctions make sense with the clinical expression. The cell or tissue tropism of such viral triggers should then determine, in a major part, the clinical symp-toms associated with such pathogenic HERV-W expression and thereby the nature of the induced disease. It may be particularly relevant for infections or herpesvirus reactivation in adult life.
Other viral, microbial or parasite infections
The two previous examples do not preclude a similar role for other agents at the origin of perinatal infections. Prenatal exposures to polio and rubella viruses have also been proposed as risk factor (Brown and Derkits 2010). They are not further discussed here, as we lack molecular evidences of a direct activation of HERV-W elements by these viruses, if ever existing. Nonetheless, other microbial agents could potentially trigger the release of pro-infl ammatory cytokines that would pass the placental barrier in an infectious context. Such cytokines could also trigger
activate HERV-W elements in, e.g., macrophage cells, and thereby trigger their localized expression in brain areas corresponding to their tropism (Perron et al. 1993). In addition, neurotropic viruses such as herpesviruses may persist in nervous cells in a state of programmed latency and be reactivated by, e.g., stress factors, thus maintaining the neurotropism of eventual “ side effects ” of their own expression on HERV elements.
The two distinct categories of such viral co-factors known to be involved in infections (i) during preg-nancy or (ii) in adult life will now be presented in a more detailed review with the main viral families having an epidemiological association with schizo-phrenia during these periods: Infl uenza viruses and Herpesviridae, which are now known to be potent transactivators of HERV-W elements. Other viral contribution, that may not be relevant for “ HERV-W associated Schizophrenia sub-group ” we are focus-ing on, will be further discussed.
Infl uenza virus
Infl uenza virus has been experimentally shown to reactivate HERV-W expression with cell-specifi c patterns modulated by environmental infl uences (Nellaker et al. 2006). Perinatal infl uenza epidemics have long been suspected to be associated with schizophrenia (Grech et al. 1997). Serologically doc-umented prenatal exposure to infl uenza established a three-fold elevation of risk of schizophrenia follow-ing infl uenza exposure during the fi rst half of gesta-tion (Brown and Derkits 2010). It is likely that Infl uenza virus plays a major role in a primary activa-tion of HERV-W during pregnancy, favouring a later onset of schizophrenia, possibly after a secondary transactivation (e.g., by CMV) in adult life. Interest-ingly, a signifi cant absence or reduction of DNA methylation occurs in early embryo cells, which increases embryonic vulnerability to an eventual acti-vation of HERV-W elements, when such methylation normally inactivates HERV copies in the adult genome (Schulz et al. 2006; Lees-Murdock and Walsh 2008). In addition, activation of HERV-W elements associated with the production of virion particles and reverse transcriptase activity (such as MSRV), as reported in schizophrenic patients (Huang et al. 2010), could induce retrotranspositions and genetic rearrangements in a particularly susceptible embryonic genome. This could possibly be at the origin of the recently reported DNA modifi cations in schizophrenic patients (Stefansson et al. 2008) and would constitute a major molecular basis for the acquisition of a risk factor determined by genetic modifi cations involving HERV-W elements and their transposable partners (Pavlicek et al. 2002).
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86 M. Leboyer et al.
possible, for a sub-group of schizophrenic patients with relevant bio-signatures such as elevated CRP and HERV-W Env antigenaemia, to outline a new framework of causes and timing which is described as follows.
Perinatal events
In utero , non-methylated HERV-W DNA retrotran-position potential can be triggered by infectious agents such as infl uenza virus or other peculiar envi-ronmental pathogens. This perinatal genetic activa-tion of HERV-W elements is consistent with a “ gene – environment hypothesis ” , since pathogeny of HERV-W is dependent upon infl ammation and epi-genetic factors. Epidemics and prevalence of infec-tions in pregnant women could be in conjunction with other known environmental factors, such as being raised in an urban environment (Eaton et al. 2000). As a consequence of this activation, HERV-W elements susceptible to encode a reverse-transcriptase enzyme altogether with other retroviral genes have the potential to retro-insert DNA copies into the embryonic DNA and to cause recombina-tions, microdeletions and copy-number variations with gene transduction, thus providing a plausible explanation for the genetic modifi cations recently found in patients with schizophrenia (Consortium 2008; Stefansson et al. 2008).
Prodromes and onset of schizophrenia
Pre-schizophrenic children may have developmental delays in motor, speech, emotional and social development, and lower general cognitive ability. In addition, brain imaging abnormalities are present in the fi rst episode of schizophrenia (Borgwardt et al. 2008) and during prodromal phases (Lappin et al. 2007), evidencing defi cits before the clinical onset with further alterations as the illness progresses (Rapoport et al. 1997). Thus, after perinatal trigger-ing events, one could assume that stress, secondary infections with neurotropic agents (such as CMV) or other environmental triggering factors could acti-vate “ perinatally modifi ed ” HERV-W copies from susceptible individuals having experienced perinatal infection with HERV-W associated modifi cations. Expression of HERV-W envelope protein (Env) reactivated in the vicinity of neuronal cells could induce the fi rst psychotic episodes as a result of its pro-infl ammatory and neurotoxic properties which would impair neurodevelopment. This is further corroborated by elevated levels of pro-infl ammatory cytokines in body fl uids of schizophrenic patients (Potvin et al. 2008). The occurrence and the inten-sity of prodromic symptoms could thus result from
non-methylated HERV-W copies in embryos (Perron and Lang 2010).
Altogether, these data suggest that HERV-W elements located in the human genome, at the inter-face between “ environmental triggers ” and “ gene responsiveness ” , may be considered as the missing link between the “ environmental triggers ” and the gene-dependent induction of a pathogenic process leading to schizophrenia.
Role of “ non HERV ” gene – environment interaction in schizophrenia
While infectious exposure can be viewed as an important environmental factor reactivating HERV-W elements, variability in responses to such infections is also the rule. It indicates that the out-come of primary pathogenic events also depends upon factors such as the maternal immune response to infection and the genetic background of the patient, which makes sense with the infl uence of peculiar immunogenetic alleles. Both may also act as modulators of the immune response and may thus interfere with pathogen-driven activation of HERV-W elements. Indeed, two recent studies over 8000 cases reported associations between schizo-phrenia and single nucleotide polymorphism (SNP) in, or close to, major histocompatibility complex (MHC) on chromosome 6 (Shi et al. 2009; Stefans-son et al. 2009). These observations follow a long history implying HLA in schizophrenia. Since the early seventies, several studies have found evidences of association between HLA polymorphisms and schizophrenia (Schwab et al. 1995; Straub et al. 1995). In particular, association between HLA-A9, A10 (Asaka et al. 1981) and DRB1 (Sasaki et al. 1999) have been reported in different ethnic popula-tion, but discrepancies between genetic studies have been the rule. The presence of HERV-W copies inserted in these regions of chromosome 6 (Alliel et al. 2002) and their inter-ethnic (if not inter-individ-ual) variations (Mirsattari et al. 2001) could offer an explanation for such differences in targeted interac-tions with HLA genes. Fine dissection of HLA “ interaction ” with schizophrenia will certainly favour the entry/come back of the disease in the “ immuno-logical disorders club ” .
HERV-W and the natural history of schizophrenia: a conceptual framework for causes and timing
If one assumes that endogenous retroviral elements are the missing link between (i) peri-natal and later infectious events and (ii) genetic factors, it becomes
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HERV-W and schizophrenia 87
cascades converging towards the pivotal following factor; and (3) abnormal and chronic increase of HERV-W Env protein expression, which immuno-infl ammatory and neuropathogenic effects might be initiated as early as in embryonic life (genetic modi-fi cations linked to activation of retrotransposable elements) by perinatal infections and later stimu-lated in key cerebral regions by secondary infections or various stresses.
At the tissue and cellular level, since microglial cells are pivotal at the interface of infl ammation and neurotoxicity in the central nervous system and, in particular in brain grey matter, they would most probably be involved in such pathogenic effects (Sugama et al. 2009). This would be consistent, here, with the previously described expression of HERV-W Env protein in microgliocytes within neu-roinfl ammatory lesions (Perron et al. 2005). A sim-ilar study is now envisaged in brain sections obtained from schizophrenia and control cases.
The replication and the extension of our fi rst results (Perron et al. 2008) through large-scale trans-versal and longitudinal bioclinical studies exploring the role of HERV-W in infl ammation and neurotox-icity of schizophrenic disorders is required. It is the purpose of a concerted study presently associating the Authors. This should open a better understand-ing in lifelong evolution of relationships intermin-gling HERV-W elements, environmental factors, immuno-genetics, progression of the disease, and identifi cation of new promising targets.
Of note, the existence of a proportion of HERV-W negative schizophrenic patients reported in all inde-pendent studies is suggestive of other etiological agents in other sub-groups. Among them, Borna dis-ease viruses have long been studied despite discrep-ancies in results (Taieb et al. 2001; Na et al. 2009; Heinrich and Adamaszek 2010). However, Horie and colleagues recently showed that, like HERV-W, bornaviruses may have endogenized in our ancestors (Horie et al. 2010), thus constituting a possible alter-native “ endogenous-viral link ” between genes and environment in schizophrenia.
However, new therapeutic issues may not pre-clude antipsychotic drugs treatments that might also reveal synergistic, considering their reported anti-infl ammatory properties (Kato et al. 2007, 2008; Zheng et al. 2008). Nonetheless, primary anti-infl ammatory therapy has been proposed in face of infl ammatory features in schizophrenia (Berthold-Losleben et al. 2009). If chronically administered, this may raise the same concerns as now well docu-mented in chronic infl ammatory diseases such as rheumatoid arthritis or multiple sclerosis, where chronic or repeated immunosuppression has yielded a signifi cantly problematic number of side effects,
both genetically dysregulated expression of HERV-W Env and from resulting microdeletions or gene duplications affecting brain cell activity. This fi ts nicely with the notion that the density of “ copy num-ber variations ” (CNV) found in schizophrenic patients, parallels the severity of the symptoms (Walsh et al. 2008).
Episodic and deteriorating evolution
The following episodic and deteriorating evolution of the disorder would later be linked to the repeated occurrence of “ stressful ” events being able to re-activate HERV-W including, for example, viral intrusions in certain brain areas (e.g., with cytomeg-alovirus, a member of the Herpesviridae) that have been associated with schizophrenia during adult life (Torrey et al. 2006). Immuno-infl ammatory and neurotoxic effects of HERV-W Env protein might underlie brain cortical thinning observed by neuro-imaging and progressive cognitive decline (Bornstein et al. 1992). Interestingly, psychotic episode have been shown to be preceded by raised levels of immune cytokines in the cerebrospinal fl uid (McAl-lister et al. 1995).
Therefore, as the theory that infections play a causal role in schizophrenia fi nds its origin at the dawn of Biological Psychiatry (Lycke et al. 1974; Chacon et al. 1975), the picture now appears more complex than mere effects of given infectious agents. Our novel hypothesis proposes a temporal succession of infectious priming and triggering events interact-ing with peculiar genes belonging to the (retro-)trans-posable “ half ” of the human genome, modulated by immuno-genetic factors, which would initiate patho-genic events triggering and “ fueling ” successive cas-cades of genetic, infl ammatory and neurotoxic effects. This would fi t with most, if not all, dispersed pieces of the Puzzle represented by data from the many domains of research on schizophrenia.
Perspectives and new therapeutic avenues
If we consider key events and periods with different clinical expression in a synthetic scenario explaining the aetiopathogeny of schizophrenia, at least in its neuro-infl ammatory and neuro-toxic forms, we can depict (as schematized in Figure 3): (1) an infectious and/or major infl ammatory event during pregnancy; (2) secondary infections with neurotropic agents (such as CMV), as well as reactivation of latent neurotropic agents induced by various stresses (including Herpesviridae such as CMV or HSV, but also latent cerebral Toxoplasma gondii infections, etc.) occurring later in life, implicating reactivations
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120 with its cellular receptor CD4 by matrix-assisted laser desorption/ionization mass spectrometry. Biochemistry 38: 11734 – 11740.
Borgwardt SJ, McGuire PK, Aston J, Gschwandtner U, Pfl uger MO, Stieglitz RD, et al. 2008. Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophr Res 106:108 – 114.
Bornstein RA, Schwarzkopf SB, Olson SC, Nasrallah HA. 1992. Third-ventricle enlargement and neuropsychological defi cit in schizophrenia. Biol Psychiatry 31:954 – 961.
Bradford RD, Pettit AC, Wright PW, Mulligan MJ, Moreland LW, McLain DA, et al. 2009. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 49:924 – 927.
Brown AS, Derkits EJ. 2010. Prenatal infection and schizophre-nia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261 – 280.
Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman JM, et al. 2001. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry 49: 473 – 486.
Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. 2004. Serologic evidence of prenatal infl u-enza in the etiology of schizophrenia. Arch Gen Psychiatry 61:774 – 780.
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. 2001. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 58:1032 – 1037.
Buka SL, Cannon TD, Torrey EF, Yolken RH. 2008. Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry 63:809 – 815.
Chacon C, Monro M, Harper I. 1975. Viral infection and psy-chiatric disorders. Acta Psychiatr Scand 51:101 – 103.
Challem JJ, Taylor EW. 1998. Retroviruses, ascorbate, and muta-tions, in the evolution of Homo sapiens. Free Radic Biol Med 25:130 – 132.
Chao CC, Hu S, Ehrlich L, Peterson PK. 1995. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxic-ity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 9:355 – 365.
Consortium TIS. 2008. Rare chromosomal deletions and dupli-cations increase risk of schizophrenia. Nature 455:237 – 241.
De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, et al. 2009. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41:776 – 782.
Deb-Rinker P, Klempan TA, O ’ Reilly RL, Torrey EF, Singh SM. 1999. Molecular characterization of a MSRV-like sequence identifi ed by RDA from monozygotic twin pairs discordant for schizophrenia. Genomics 61:133 – 144.
Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Yolken RH. 2003. Reduction of symptoms by valacyclovir in cytome-galovirus-seropositive individuals with schizophrenia. Am J Psychiatry 160:2234 – 2236.
Dickerson F, Kirkpatrick B, Boronow J, Stallings C, Origoni A, Yolken R. 2006. Defi cit schizophrenia: association with serum antibodies to cytomegalovirus. Schizophr Bull 32:396 – 400.
Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. 2007. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res 93:261 – 265.
Eaton WW, Mortensen PB, Frydenberg M. 2000. Obstetric fac-tors, urbanization and psychosis. Schizophr Res 43:117 – 123.
Grech A, Takei N, Murray RM. 1997. Maternal exposure to infl u-enza and paranoid schizophrenia. Schizophr Res 26:121 – 125.
including deathly encephalitis with, e.g., JC virus (Major 2010) or herpesvirus (Bradford et al. 2009) and rapidly appearing cancers (Pace and Zajicek 2009; Lebrun et al. 2011).
In conclusion, the main interest for the medical community and obviously for the patients of this emerging research fi eld relies in the possible devel-opment of hopefully more effi cient and safer thera-peutic strategies, at least in a subgroup of schizophrenic patients.
Acknowledgments
The authors are supported by the “ Institut National de la Sant é et de la Recherche M é dicale ” (INSERM), the “ Agence Nationale pour la Recherche ” (ANR; NEURO 2009, V.I.P. project), the fondation FondaMental (Fondation de Coop é ration Scienti-fi que pour le d é veloppement de la recherche et des soins en sant é mentale), and GeNeuro Innovation, France.
Statement of Interest
Herv é Perron and Rapha ë l Faucard are fi nancially supported by GeNeuro/GeNeuro Innovation. All other authors declare that they have no confl icts of interest.
References
Alliel PM, Perin JP, Goudou D, Bitoun M, Robert B, Rieger F. 2002. The HERV-W/7q family in the human genome. Poten-tial for protein expression and gene regulation. Cell Mol Biol (Noisy-le-grand) 48:213 – 217.
Asaka A, Okazaki Y, Namura I, Juji T, Miyamoto M, Ishikawa B. 1981. Study of HLA antigens among Japanese schizophren-ics. Br J Psychiatry 138:498 – 500.
Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN. 2006. The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psy-chiatry 11:47 – 55.
Berthold-Losleben M, Heitmann S, Himmerich H. 2009. Anti-infl ammatory drugs in psychiatry. Infl amm Allergy Drug Targets 8:266 – 276.
Bhende PM, Seaman WT, Delecluse HJ, Kenney SC. 2004. The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet 36:1099 – 1104.
Blond JL, Beseme F, Duret L, Bouton O, Bedin F, Perron H, et al. 1999. Molecular characterization and placental expres-sion of HERV-W, a new human endogenous retrovirus family. J Virol 73:1175 – 1185.
Boksa P. 2010. Effects of prenatal infection on brain development and behavior: a review of fi ndings from animal models. Brain Behav Immun 24:881 – 897.
Borchers C, Tomer KB. 1999. Characterization of the noncova-lent complex of human immunodefi ciency virus glycoprotein
Wor
ld J
Bio
l Psy
chia
try
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Rye
rson
Uni
vers
ity o
n 03
/09/
13Fo
r pe
rson
al u
se o
nly.
HERV-W and schizophrenia 89
Meyer U, Feldon J. 2010. Epidemiology-driven neurodevelop-mental animal models of schizophrenia. Prog Neurobiol 90:285 – 326.
Mirsattari SM, Johnston JB, McKenna R, Del Bigio MR, Orr P, Ross RT, et al. 2001. Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica. Neurology 56:317 – 323.
Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Torrey EF, et al. 2007. Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of fi lter paper blood samples obtained at birth. Biol Psychiatry 61:688 – 693.
Na KS, Tae SH, Song JW, Kim YK. 2009. Failure to detect borna disease virus antibody and RNA from peripheral blood mononuclear cells of psychiatric patients. Psychiatry Investi 6:306 – 312.
Nawa H, Takei N. 2006. Recent progress in animal modeling of immune infl ammatory processes in schizophrenia: implication of specifi c cytokines. Neurosci Res 56:2 – 13.
Nellaker C, Yao Y, Jones-Brando L, Mallet F, Yolken RH, Karlsson H. 2006. Transactivation of elements in the human endogenous retrovirus W family by viral infection. Retrovirol-ogy 3:44.
Pace AA, Zajicek JP. 2009. Melanoma following treatment with alemtuzumab for multiple sclerosis. Eur J Neurol 16:e70 – 71.
Pachter JS, de Vries HE, Fabry Z. 2003. The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593 – 604.
Pavlicek A, Paces J, Zika R, Hejnar J. 2002. Length distribution of long interspersed nucleotide elements (LINEs) and proc-essed pseudogenes of human endogenous retroviruses: implica-tions for retrotransposition and pseudogene detection. Gene 300:189 – 194.
Perron H, Lang A. 2010. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinfl ammation. Clin Rev Allergy Immunol 39:51 – 61.
Perron H, Lalande B, Gratacap B, Laurent A, Genoulaz O, Geny C, et al. 1991. Isolation of retrovirus from patients with multiple sclerosis. Lancet 337:862 – 863.
Perron H, Suh M, Lalande B, Gratacap B, Laurent A, Stoebner P, et al. 1993. Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus har-boured by a leptomeningeal cell line from a patient with mul-tiple sclerosis. J Gen Virol 74(Pt 1):65 – 72.
Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, et al. 1997. Molecular identifi cation of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Scle-rosis. Proc Natl Acad Sci USA 94:7583 – 7588.
Perron H, Jouvin-Marche E, Michel M, Ounanian-Paraz A, Camelo S, Dumon A, et al. 2001. Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. Virology 287:321 – 332.
Perron H, Lazarini F, Ruprecht K, Pechoux-Longin C, Seilhean D, Sazdovitch V, et al. 2005. Human endogenous retrovirus (HERV)-W ENV and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions. J Neurovirol 11:23 – 33.
Perron H, Mekaoui L, Bernard C, Veas F, Stefas I, Leboyer M. 2008. Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients. Biol Psychiatry 64:1019 – 1023.
Perron H, Bernard C, Bertrand JB, Lang AB, Popa I, Sanhadji K, et al. 2009. Endogenous retroviral genes, Herpesviruses and gender in Multiple Sclerosis. J Neurol Sci 286:65 – 72.
Griffi ths DJ. 2001. Endogenous retroviruses in the human genome sequence. Genome Biol 2:1017.
Heinrich A, Adamaszek M. 2010. Anti-Borna disease virus anti-body responses in psychiatric patients: long-term follow up. Psychiatry Clin Neurosci 64:255 – 261.
Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, et al. 2009. Similar immune profi le in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis fac-tor receptor I and von Willebrand factor. Bipolar Disord 11:726 – 734.
Horie M, Honda T, Suzuki Y, Kobayashi Y, Daito T, Oshida T, et al. 2010. Endogenous non-retroviral RNA virus elements in mammalian genomes. Nature 463:84 – 87.
Huang W, Li S, Hu Y, Yu H, Luo F, Zhang Q, et al. 2011. Implication of the env gene of the human endogenous retrovi-rus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. Schizophr Bull 37:988 – 1000.
Jia P, Wang L, Meltzer HY, Zhao Z. 2010. Common variants conferring risk of schizophrenia: a pathway analysis of GWAS data. Schizophr Res 122(1 – 3):38 – 42.
Karlsson H, Bachmann S, Schroder J, McArthur J, Torrey EF, Yolken RH. 2001. Retroviral RNA identifi ed in the cerebros-pinal fl uids and brains of individuals with schizophrenia. Proc Natl Acad Sci USA 98:4634 – 4639.
Karlsson H, Schroder J, Bachmann S, Bottmer C, Yolken RH. 2004. HERV-W-related RNA detected in plasma from indi-viduals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry 9:12 – 13.
Kato T, Monji A, Hashioka S, Kanba S. 2007. Risperidone sig-nifi cantly inhibits interferon-gamma-induced microglial activa-tion in vitro. Schizophr Res 92:108 – 115.
Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y, et al. 2008. Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellu-lar Ca2 � regulation in vitro. J Neurochem 106:815 – 825.
Kumpfel T, Hohlfeld R. 2009. Multiple sclerosis. TNFRSF1A, TRAPS and multiple sclerosis. Nat Rev Neurol 5:528 – 529.
Lappin JM, Dazzan P, Morgan K, Morgan C, Chitnis X, Suckling J, et al. 2007. Duration of prodromal phase and severity of volumetric abnormalities in fi rst-episode psychosis. Br J Psy-chiatry Suppl 51:s123 – 127.
Lebrun C, Vermersch P, Brassat D, Defer G, Rumbach L, Clavelou P, et al. 2011. Cancer and multiple sclerosis in the era of disease-modifying treatments. J Neurol 258:1304 – 11.
Lees-Murdock DJ, Walsh CP. 2008. DNA methylation repro-gramming in the germ line. Epigenetics 3:5 – 13.
Lycke E, Norrby R, Roos BE. 1974. A serological study on men-tally ill patients with particular reference to the prevalence of herpes virus infections. Br J Psychiatry 124:273 – 279.
Mack M, Kleinschmidt A, Bruhl H, Klier C, Nelson PJ, Cihak J, et al. 2000. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodefi ciency virus 1 infection. Nat Med 6:769 – 775.
Major EO. 2010. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 61:35 – 47.
McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, et al. 1995. Increases in CSF levels of inter-leukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 152:1291 – 1297.
Menard A, Amouri R, Michel M, Marcel F, Brouillet A, Belliveau J, et al. 1997. Gliotoxicity, reverse transcriptase activity and ret-roviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis. FEBS Lett 413:477 – 485.
Wor
ld J
Bio
l Psy
chia
try
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Rye
rson
Uni
vers
ity o
n 03
/09/
13Fo
r pe
rson
al u
se o
nly.
90 M. Leboyer et al.
Sugama S, Takenouchi T, Cho BP, Joh TH, Hashimoto M, Kitani H. 2009. Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Infl amm Allergy Drug Targets 8:277 – 284.
Swaminathan B, Matesanz F, Cavanillas ML, Alloza I, Otaegui D, Olascoaga J, et al. 2010. Validation of the CD6 and TNFRSF1A loci as risk factors for multiple sclerosis in Spain. J Neuroimmunol 223:100 – 103.
Taieb O, Baleyte JM, Mazet P, Fillet AM. 2001. Borna disease virus and psychiatry. Eur Psychiatry 16:3 – 10.
Torrey EF, Miller J, Rawlings R, Yolken RH. 1997. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 28:1 – 38.
Torrey EF, Leweke MF, Schwarz MJ, Mueller N, Bachmann S, Schroeder J, et al. 2006. Cytomegalovirus and schizophrenia. CNS Drugs 20:879 – 885.
van Os J, Murray R. 2008. Gene-environment interactions in schizophrenia. Introduction. Schizophr Bull 34:1064 – 1065.
Vilela MC, Lima GK, Rodrigues DH, Lacerda-Queiroz N, Mansur DS, de Miranda AS, et al. 2010. TNFR1 plays a critical role in the control of severe HSV-1 encephalitis. Neu-rosci Lett 479:58 – 62.
Voisset C, Blancher A, Perron H, Mandrand B, Mallet F, Paranhos-Baccala G. 1999. Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates. AIDS Res Hum Retroviruses 15:1529 – 1533.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, et al. 2008. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophre-nia. Science 320:539 – 543.
Yao Y, Schroder J, Nellaker C, Bottmer C, Bachmann S, Yolken RH, et al. 2008. Elevated levels of human endogenous retrovirus-W transcripts in blood cells from patients with fi rst episode schizophrenia. Genes Brain Behav 7:103 – 112.
Yolken RH, Karlsson H, Yee F, Johnston-Wilson NL, Torrey EF. 2000. Endogenous retroviruses and schizophrenia. Brain Res Brain Res Rev 31:193 – 199.
Zheng LT, Hwang J, Ock J, Lee MG, Lee WH, Suk K. 2008. The antipsychotic spiperone attenuates infl ammatory response in cultured microglia via the reduction of proinfl ammatory cytokine expression and nitric oxide production. J Neurochem 107:1225 – 1235.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. 2008. Infl ammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63:801 – 808.
Rapoport JL, Giedd J, Kumra S, Jacobsen L, Smith A, Lee P, et al. 1997. Childhood-onset schizophrenia. Progressive ven-tricular change during adolescence. Arch Gen Psychiatry 54: 897 – 903.
Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN. 2006. The envelope protein of a human endog-enous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol 176:7636 – 7644.
Sasaki T, Matsushita M, Nanko S, Fukuda R, Kennedy JL, Tokunaga K. 1999. Schizophrenia and the HLA-DRB1 gene in the Japanese population. Am J Psychiatry 156:771 – 773.
Schulz WA, Steinhoff C, Florl AR. 2006. Methylation of endog-enous human retroelements in health and disease. Curr Top Microbiol Immunol 310:211 – 250.
Schwab SG, Albus M, Hallmayer J, Honig S, Borrmann M, Lich-termann D, et al. 1995. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat Genet 11:325 – 327.
Serra C, Mameli G, Arru G, Sotgiu S, Rosati G, Dolei A. 2003. In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis. J Neurovirol 9:637 – 643.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe ' er I, et al. 2009. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753 – 757.
Short SJ, Lubach GR, Karasin AI, Olsen CW, Styner M, Knickmeyer RC, et al. 2010. Maternal infl uenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol Psychiatry 67:965 – 973.
Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. 2008. Large recurrent microdeletions associ-ated with schizophrenia. Nature 455:232 – 236.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. 2009. Common variants conferring risk of schizophrenia. Nature 460:744 – 747.
Straub RE, MacLean CJ, O ’ Neill FA, Burke J, Murphy B, Duke F, et al. 1995. A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity. Nat Genet 11:287 – 293.
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