Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness

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Science  02 Jul 2015:
DOI: 10.1126/science.aab3369

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The global spread of dengue virus (DENV) infections has increased viral genetic diversity, some of which appear associated with greater epidemic potential. The mechanisms governing viral fitness in epidemiological settings, however, remain poorly defined. We identified a determinant of fitness in a foreign dominant (PR-2B) DENV serotype 2 (DENV-2) clade, which emerged during the 1994 epidemic in Puerto Rico and replaced an endemic (PR-1) DENV-2 clade. The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication. PR-2B sfRNA showed sequence-dependent binding to and prevention of tripartite motif 25 (TRIM25) deubiquitylation, which is critical for sustained and amplified RIG-I-induced type-I interferon expression. Our findings demonstrate a unique viral RNA-host protein interaction to evade the innate immune response for increased epidemiological fitness.

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