期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 50, 页码 21641-21646出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1011998107
关键词
persistent viral infections; viral polymerase; plasmacytoid dendritic cell; viral tropism; acquired immunodeficiency syndrome
资金
- Boehringer Ingelheim Fonds
- Roche Research Foundation
- Schweizerische Stiftung fur Medizinisch-Biologische Stipendien foundation of the Swiss National Science Foundation
- Australian National Health
- Medical Research Council
- Volkswagen Foundation
- Swiss National Science Foundation [3100A0-104067/1, PP00A-114913/1]
- European Community
- Prix Scientifique of the Fondation Leenaards
The Clone 13 (Cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. Here, we used reverse genetic techniques to identify the molecular basis of Cl13 persistence and immunosuppression, the characteristics differentiating it from the closely related Armstrong strain. We found that a single-point mutation in the Cl13 polymerase was necessary and partially sufficient for viral persistence and immunosuppression. A glycoprotein mutation known to enhance dendritic cell targeting accentuated both characteristics but when introduced alone, failed to alter the phenotype of the Armstrong strain. The decisive polymerase mutation increased intracellular viral RNA load in plasmacytoid dendritic cells, which we identified as a main initial target cell type in vivo, and increased viremia in the early phase of infection. These findings establish the enhanced replicative capacity as the primary determinant of the Cl13 phenotype. Viral persistence and immunosuppression can, thus, represent a direct consequence of excessive viral replication overwhelming the host's antiviral defense.
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