Dendritic cell subversion permits viral persistence (VIR1P.959)

Abstract

Abstract Persistent viral infections share the ability to combat the normally protective function of dendritic cells (DC). We and others postulate that DC inhibition is necessary for viruses to persist in spite of an adaptive T cell response (e.g. HIV, HBV, and HCV). However, resolving whether viral subversion of DC (directly or indirectly) actually permits systemic viral persistence in vivo has not been determined. We developed a model system that allows us to inhibit viral replication in specific cell types to answer this question. We used cell-specific genetic deletion of the host site-1 protease (S1P) to determine a requirement for DC infection in viral persistence. The host site-1 protease (S1P) is required for replication of lymphocytic choriomeningitis virus (LCMV) and other hemorrhagic arenaviruses in addition to HCV replication. We deleted S1P in DC (S1PDCnull) to selectively eliminate viral replication in DC. Three weeks post LCMV infection, S1PDCnull mice had NO detectable viremia in contrast to >5 logs of infectious virus present in WT controls. Thus, productive infection of DC was required for viral persistence. This genetic deletion occurs in <1% of the cells LCMV infects. Thus, overall viral loads were equivalent during the 1st week of infection between WT and S1PDCnull mice. However, S1PDCnull mice possessed more polyfunctional T cells which we reason led to a rapid loss of viral persistence.