Herpesviruses, Endogenous Retroviruses and Human Neuropsychiatric Diseases

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Herpesviruses, Endogenous Retroviruses and Human Neuropsychiatric Diseases

Presented by Robert Yolken MD¹, E Fuller Torrey MD², Faith Dickerson³ PhD
¹Johns Hopkins School of Medicine, Baltimore Md ²Stanley Medical Research Institute, Bethesda Md. ³Sheppard Pratt Health System, Baltimore Md.

Schizophrenia and bipolar disorder are pervasive human diseases with high rates of morbidity and mortality worldwide. Most cases are first evident during late adolescence or early adulthood and have a lifelong course. These diseases are thus associated with an extraordinary social and economic burden. Despite recent advances in the fields of neurogenetics and neurochemistry, the aetiology of most cases of schizophrenia and bipolar disorder remains enigmatic.
We have found in previous studies that approximately 30% of individuals with schizophrenia have evidence of the transcription of the endogenous retroviruses HERV-W in their cerebrospinal fluid.¹ These endogenous elements are the result of the retrotransposition of ancient retroviruses into the genome of human progenitors; they are probably not capable of active infection. However, the proteins encoded by the endogenous retroviruses sequences in the human genome have retained a number of biological functions. For example, the envelope protein of HERV-W is capable of promoting cell fusion and syncytial cell formation during normal fetal development.² Aberrant transcription and translation of this protein may contribute to pathological fetal states such as pre-eclampsia.³ The envelope protein generated by HERV-W also binds to a number of cell-surface molecules within the central nervous system, including the neutral amino acid transporter ASCT-2.⁴ This molecule is a major transporter of glutamine within neural tissues.⁵ The transcription of HERV-W envelope may result in an alteration in the brain level of glutamine and glutamine metabolites, thus contributing to the alterations in glutamatergic function which constitute one of the principal biochemical abnormalities found in the brains of individuals with schizophrenia and bipolar disorder.⁶
It is difficult to directly measure the activity of endogenous retroviruses in blood or other clinical samples obtainable from large numbers of individuals by non-invasive techniques. Human herpesviruses have been shown to activate endogenous retroviruses in cell culture.⁷ We have hypothesized that human herpesviruses may be one of the activators of endogenous retroviruses in humans, and have explored the association between infection with human herpesviruses and psychiatric diseases. We have found an increased rate of antibodies to cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) in some populations of young individuals with recent onset of schizophrenia. While we have not found an increased prevalence of these antibodies in older individuals with stable forms of schizophrenia or bipolar disorder, we have found that individuals with these diseases, who have serological evidence of infection with HSV-1, or to a lesser extent, CMV, have significant levels of cognitive impairment, particularly in the domain of immediate memory.⁸ We have not found an association between serological evidence of herpesvirus infection and cognitive functioning in control populations without psychiatric disorders.
We further explored the possible role of human herpesviruses as contributing factors in schizophrenia, by the performance of a treatment trial in which individuals with schizophrenia were administered valaciclovir over a 16-week period of time. We found that individuals who were seropositive for CMV displayed a significant improvement in symptoms during the course of the trial (P<0.0005, repeated measures analysis of variance). There was also some improvement in psychotic symptoms in individuals who were seropositive for HSV-1. Further studies to examine the role of antiviral treatment on the symptoms of schizophrenia are ongoing. These studies may serve to define the role of human herpesviruses in the aetiopathogenesis of schizophrenia and bipolar disorder, as well as to define new therapies for the prevention and treatment of these devastating and disabling disorders.

References
1. Karlsson H, Bachmann S, Schroder J, McArthur J, Torrey EF, Yolken RH. PNAS 2001;98:4634–4639.
2. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L. Nature 2000;403: 785–789.
3. Lee X, Keith JC, Jr, Stumm N, Moutsatsos I, McCoy JM, Crum CP. Placenta 2001;22:808–812.
4. Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D. J Virol 2002; 76:6442–6452.
5. Broer S, Brookes N. J Neurochem 2001;77:705–719.
6. Tsai G, Coyle JT. Ann Rev Pharmacol Toxicol 2002;42:165–179.
7. Perron H, Perin JP, Rieger F, Alliel PM. J Neurovirol 2000;6(Suppl 2):S67–S75.
8. Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Arch Gen Psychiatry 2003 (in press).

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