James H McLinden, Nirjal Bhattarai, Jack T Stapleton, Qing Chang, Thomas M Kaufman, Suzanne L Cassel, Fayyaz S Sutterwala, Hillel Haim, Jon C Houtman, Jinhua Xiang

The Flavivirus genus within the Flaviviridae is comprised of many important human pathogens including Yellow Fever virus (YFV), Dengue virus (DENV) and Zika virus (ZKV), all of which are global public health concerns. Although the related flaviviruses hepatitis C virus and human pegivirus (formerly named GBV-C) interfere with T cell receptor (TCR) signaling by novel RNA and protein based mechanisms, the effect of other flaviviruses on TCR signaling is unknown. Here, we studied the effect of YFV, DENV, and ZKV on TCR signaling. Both YFV and ZKV replicated in human T cells in vitro; however, only YFV inhibited TCR signaling. This effect was mediated at least in part by the YFV envelope (env) protein coding RNA. Deletion mutagenesis studies demonstrated that expression of a short, YFV env RNA motif (vsRNA) was required and sufficient to inhibit TCR signaling. Expression of this vsRNA and YFV infection of T cells reduced the expression of Src-kinase regulatory phosphatase (PTPRE), while ZKV infection did not. YFV infection in mice resulted in impaired TCR signaling and PTPRE expression, with associated reduction in murine response to experimental ovalbumin vaccination. Together, these data suggest that viruses within the flavivirus genus inhibit TCR signaling in a species-dependent manner.