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Novel approaches and challenges to treatment of central nervous system viral infections

Authors

  • Avindra Nath MD,

    1. Section of Infections of the Nervous Systems, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD
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  • Kenneth L. Tyler MD

    Corresponding author
    1. Departments of Neurology, Microbiology, and Medicine, University of Colorado School of Medicine, Aurora, CO
    2. Neurology Service, Denver Veterans Administration Medical Center, Denver, CO
    • Address correspondence to Dr Tyler, Neurology Mailstop B-182, University of Colorado School of Medicine, Research Complex-2, 12700 East 19th Ave, Aurora, CO 80045. E-mail: ken.tyler@ucdenver.edu

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Abstract

Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available, including candidate thiazolide and pyrazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antiviral agents and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T lymphocytes has been used in humans and may provide an effective therapy for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. Ann Neurol 2013;74:412–422

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