Early events dependent on the suppression of IPS signaling are necessary for persistent viral infection (P6300)

Abstract

Abstract Persistent infections are characterized by evasion of innate and adaptive immune responses controlled by the upregulation of immunosuppressive cytokines. However, little is known whether events during the first day of infection form the environment necessary for the establishment of a persistent infection. Using a novel in vivo competition approach by priming a persistent lymphocytic choriomenengitis virus (LCMV) infection with a non-propagating LCM virus, we found that suppression of the intracellular RNA sensing pathway and not the TLR7 pathway is necessary for establishing a persistent infection. Furthermore, signaling through IPS/MAVS up to six hours before LCMV inoculation changes the nature of the immune response within the first 24 hours. Increased cytokine expression, normally observed in the first 18-24 hours during a persistent LCMV infection, is markedly reduced upon priming. Reduced cytokine expression is associated with complete clearance of the virus within 2 weeks, suggesting that LCMV initiates persistence through immune disregulation. Interestingly, localization of viral antigen in the spleen is markedly different in primed and unprimed mice despite similar viral titers in the serum and organs three days post-infection. Thus, our data are the first to document how early events after LCMV inoculation serve to establish persistent infection and suggest that early intervention can modify the pathogenesis and course of a persistent infection.