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Endogenous retroviruses and schizophrenia

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Abstract

Retroviruses are biologically complex infectious agents which are capable of cellular infection and subsequent integration into the host genome. Retroviruses can exist in an endogenous form in which viral sequences are integrated into the human germline and are vertically transmitted in a Mendelian fashion. The transcriptional activation of these viral sequences in cells within the central nervous system can affect the transcriptional regulation of adjacent genes and result in alterations of neural functioning. This report discusses evidence for a possible role of endogenous retroviruses in the etiopathogenesis of schizophrenia and other human brain diseases. Evidence of endogenous retrovirus activity is manifested by the identification of viral sequences in the brains and cerebrospinal fluids of affected individuals. In addition, affected individuals display evidence of increased activity of virally-encoded reverse transcriptase. The identification of a retroviral component of schizophrenia would be consistent with genetic, environmental, and neurodevelopmental aspects of the disease process. The delineation of a role for retroviruses in disease pathogenesis might lead to new methods for the diagnosis and treatment of schizophrenia.

Introduction

Schizophrenia is a complex neuropsychiatric disease of uncertain etiology. Family and adoption studies have indicated that there is a significant genetic component to the pathogenesis of schizophrenia. However, despite extensive linkage analyses, there have been no genes identified which display a strong association with disease acquisition or with the clinical course of disease in affected individuals [21].

Epidemiological studies have also identified a number of environmental factors which are associated with the development of schizophrenia in some individuals. These include winter–spring birth, upbringing in an urban area, and perinatal complications. While the relative risk of these factors is less than that of having a first degree relative with schizophrenia, the high prevalence of these factors results in a large attributable risk in terms of disease association. The identification of environmental factors is not necessarily in conflict with the concept that genetic factors play an important role in the pathogenesis of schizophrenia since susceptibility to environmental factors may be under genetic control 1, 15, 39. For example, susceptibility to infection with the human retrovirus human immunodeficiency virus (HIV) is determined, to a great extent, by polymorphisms in the CCR5 monokine receptor and other molecules which serve as cell-surface co-receptors for viral attachment and entry 11, 28. Human retrovirus infection can be considered an example of an environmental event the outcome of which is determined, to a great extent, by genetically determined susceptibility and resistance mechanisms. A potential role for retroviruses in the pathogenesis of schizophrenia would thus be consistent with the concept that complex human brain diseases represent the interaction of both genetic and environmental factors [39].

There are a number of additional reasons why retroviruses are of interest in the study of the etiopathogenesis of schizophrenia. Retroviruses can infect brain cells, integrate into their cellular DNA, and cause long-term alterations in brain function 3, 32. Humans infected with the retroviruses HIV and Human T Cell Leukaemia Virus (HTLV) can display a range of psychiatric symptoms including psychosis, mania, cognitive impairment and severe depression 24, 26, 37. It is also of note that metabolites of the atypical anti-psychotic drug clozapine can inhibit the in vitro replication of laboratory strains of HIV [6]. In addition, the timing of retroviral infection is of interest in regards to the neurodevelopmental components of disease pathogenesis [8]. While retroviral infection can occur at any time in life, many endogenous retroviruses are differentially active during fetal development 13, 14, 30. Brain retroviral activation and reintegration during the pre-natal and early post-natal periods may result in alterations in brain function later in life 10, 22.

Section snippets

Biology of endogenous retroviruses

Retroviruses can exist in several different forms in vertebrate hosts. De novo infection is generally initiated by the entry of retroviral particles into susceptible cells. Retroviral particles, containing diploid RNA genomes, form a haploid DNA provirus due to the action of the viral enzyme reverse transcriptase. The provirus becomes integrated into the genome of the infected cell by the action of virally-encoded integrase enzymes. Whenever the germline cells of a host contain integrated

Potential role of ervs in the pathogenesis of human diseases

Endogenous retroviruses are well-recognized as causes of a range of disease processes in naturally and experimentally infected animals. Consequences of ERV infection in animals include neoplasia, auto-immunity, encephalitis, and fetal malformations 22, 40. The pathogenic mechanisms by which ERVs cause disease, and the role of ERV-related mechanisms in human disease have been the subject of a number of recent investigations 23, 34.

The potential mechanisms by which ERVs can cause human disease

Evidence for a retroviral involvement in schizophrenia

We have used the reverse-transcription polymerase chain reaction (RT-PCR) to investigate the hypothesis that endogenous retroviruses are associated with some cases of schizophrenia and bipolar disorder. We have employed degenerate primers homologous to two regions of the retroviral polymerase (pol) gene that are very conserved among all retroviral species (Fig. 2). These primers have been shown to amplify the pol gene of known retroviruses as well as previously unknown species [33].

These

Conclusion

Endogenous forms of human retroviruses and other retrotransposon elements are expressed in brain tissues of individuals with schizophrenia and other neuropsychiatric diseases. Retroviral expression appears to be quantitatively and qualitatively different from that which occurs in unaffected individuals. The elucidation of the role of retroviruses in schizophrenia and related diseases might represent a major advance in our understandings of these disorders. In addition, the documentation of a

Acknowledgements

This work was supported by the Theodore and Vada Stanley Foundation.

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