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Journal of Virology, April 2008, p. 3369-3380, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02243-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

Departments of Immunology,¹ Neurology, Mayo Clinic, Rochester, Minnesota 55905²

Received 16 October 2007/ Accepted 16 January 2008

We evaluated the participatory role of human HLA-DR molecules in control of virus from the central nervous system and in the development of subsequent spinal cord demyelination. The experiments utilized intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), a picornavirus that, in some strains of mice, results in primary demyelination. We studied DR2 and DR3 transgenic mice that were bred onto a combined class I-deficient mouse (beta-2 microglobulin deficient; β2m⁰) and class II-deficient mouse (Aβ⁰) of the H-2^b background. Aβ⁰.β2m⁰ mice infected with TMEV died within 18 days of infection. These mice showed severe encephalomyelitis due to rapid replication of virus genome. In contrast, transgenic mice with insertion of a single human class II major histocompatibility complex (MHC) gene (DR2 or DR3) survived the acute infection. DR2 and DR3 mice controlled virus infection by 45 days and did not develop spinal cord demyelination. Levels of virus RNA were reduced in HLA-DR transgenic mice compared to Aβ⁰.β2m⁰ mice. Virus-neutralizing antibody responses did not explain why DR mice survived the infection and controlled virus replication. However, DR mice showed an increase in gamma interferon and interleukin-2 transcripts in the brain, which were associated with protection. The findings support the hypothesis that the expression of a single human class II MHC molecule can, by itself, influence the control of an intracerebral pathogen in a host without a competent class I MHC immune response. The mechanism of protection appears to be the result of cytokines released by CD4⁺ T cells.

Published ahead of print on 30 January 2008.