Reduced dengue virus pre-membrane protein-HMGB1 interaction activates host cell transcription to attenuate infection

To successfully complete an infection lifecycle, viruses have to avoid activating host antiviral and transcriptional responses to avoid disrupting cellular processes and cause premature host cell death. How the host transcriptional response to dengue virus (DENV) infection and its impact on pathogenesis, however, remain unclear. Herein, we examined a pair of DENV-2, where the wild-type strain (16681) elicited few host transcriptional responses following infection, in contrast to its clinically tested attenuated derivative (PDK53 strain). Site-directed mutagenesis studies revealed a single D29V substitution on the pre-membrane (prM) protein, present not in 16681 but in PDK53, that altered transcriptional response to infection. Mechanistically, prM D29V substitution impaired interaction of prM protein with host high mobility group box 1 (HMGB1) protein; wild-type prM-HMGB1 interaction prevented HMGB1 cytoplasmic-nuclear translocation to support transcriptional response to infection. Remarkably, HMGB1 knockdown not only reduced transcriptional response but also slowed virus replication rate, suggesting that HMGB1 also controlled the expression of host factors necessary for DENV replication. Indeed, introducing 29 V to prM increased virus replication rate and transcription of antiviral response genes in both wild-type DENV-3 as well as chimeric DENV-3/-2, the DENV-3 component of TAK-003. Our findings suggest exploiting this interaction to improve immunogenicity and potentially efficacy of current vaccines.