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Mechanisms and Consequences of Viral Persistence in the CNS

I. Novella, M. Watanabe, S. Gonzalez, B. Cubitt, J.C. de la Torre

Epidemiologic and clinical data, together with virologic studies, have provided evidence that viruses can establish chronic infections in the CNS. Viral persistence in the CNS can cause progressive neurologic disorders with diverse pathologic characteristics. These findings have led to the hypothesis that viruses can contribute to human mental diseases of unknown etiology. Therefore, determining the mechanisms by which viruses persist in the CNS and affect brain function is of paramount importance to human health.

We are using infection with Borna disease virus (BDV) or lymphocytic choriomeningitis virus (LCMV) as model systems to investigate these virus-host interactions. Both BDV and LCMV can persist in the brain and induce CNS disturbances manifested by cognitive and behavioral abnormalities. Studies on these viral systems are contributing to the elucidation of virus-cell interactions in the CNS that can lead to immune-mediated damage, neurodevelopmental abnormalities, and alterations in cell-differentiated functions that affect brain homeostasis.

We are currently investigating the mechanisms whereby persistence of BDV in the brain in rats causes disturbances in the postnatal maturation of the cerebellum and hippocampus. BDV persistence in the CNS is associated with a chronic and prominent astrocytosis. Hence, we are studying the effects on brain function of BDV-induced changes in gene expression in astrocytes. We are also investigating the mechanisms by which LCMV persistence in neurons alters synaptic plasticity and cognitive functions in mice without destroying brain cells.

BDV has a nonsegmented, negative-stranded RNA genome with an organization characteristic of Mononegavirales. However, BDV differs from all other known negative-stranded RNA animal viruses in several aspects. For example, BDV has a nuclear site for the replication and transcription of its genome, uses RNA splicing to regulate expression of its genes, and has a novel way of processing the viral surface glycoprotein. Because of its unique features, BDV is considered the prototype of a new virus family: Bornaviridae. LCMV is the prototypic member of the family Arenaviridae, viruses with a segmented negative-stranded RNA genome, which includes human pathogens such as Lassa fever virus.

Because of recently developed procedures, reverse genetic approaches can now be used to manipulate the genome of negative-stranded RNA viruses. We are using this experimental approach to investigate the cis- and trans-acting factors implicated in the control of viral replication and gene expression. The ability to generate specific mutations within the BDV and LCMV genomes and then analyze the phenotypic expression of these mutations will enhance our knowledge of the mechanisms that underlie CNS persistence of nonlytic viruses and the disorders associated with these viruses.

Seroepidemiologic data and recent molecular epidemiologic studies indicate that the host range, prevalence, and geographic distribution of BDV are broader than previously thought. The virus can infect humans and appears to be associated with certain human neuropsychiatric disorders. Recently, we and others detected BDV RNA and antigen in the CNS of neuropsychiatric patients. The possible role of BDV in human mental disorders and the prospect of finding other BDV-like emerging viruses, some of which may be clinically relevant, provide further impetus for the investigation of this infectious agent. Moreover, progress in the understanding of the molecular biology of BDV and LCMV should facilitate the design of effective antiviral therapies to combat these infectious agents.

PUBLICATIONS

Cubitt, B., de la Torre, J.C. Amantadine does not have antiviral activity against Borna disease virus. Arch. Virol. 142:2035, 1997.

Gonzalez-Dunia, D., Cubitt, B., de la Torre, J.C. Mechanism of Borna disease virus entry into cells. J. Virol. 72:783, 1998.

Gonzalez-Dunia, D., Sauder, C., de la Torre, J.C. Borna disease virus and the brain. Brain Res. Bull. 44:647, 1997.

Sauder, C., de la Torre, J.C. Sensitivity and reproducibility of RT-PCR to detect Borna disease virus (BDV) RNA in blood: Implications for BDV epidemiology. J. Virol. Methods, in press.