It is important to understand how viruses subvert host immunity to persist so that strategies can be developed to effectively target and purge them. T cells are critical to control persistent virus infections and the bulk of research has focused on how they achieve (or fail to achieve) this goal. However, antibodies are also a central component of the antiviral immune response against virus infections and are critical to control persistent viruses. Antibodies limit virus infection by blocking de novo cell infection and by killng infected cells;thus, suppression of antibody effector activity could severely hinder immune control of persistent virus infections. Yet, to date, specific suppression of antibody activity itslf has not been identified. Using the lymphocytic choriomeningitis virus (LCMV) model of persistent infection, we recently made the discovery that antibody effector function is suppressed during viral persistence. As a result, otherwise highly efficacious antibody mediated killing is ineffective during a persistent virus infection. Thus, we have uncovered a novel mechanism of immunosuppression during persistent infection and we hypothesize that by impeding killing of infected cells, the suppression of antibody activity facilitates viral persistece. The proposed study will (1) identify the cellular mechanisms underlying the loss of antibody effector function;(2) define how inhibition of function differentially impacts neutralizing and no-neutralizing antiviral antibodies to kill infected cells and control persistent virus infection;an (3) develop a strategy to restore antibody effector activity in vivo. Ultimately, these studies will define a previously unrecognized mechanism of immunosuppression during viral persistence and design an approach to restore antibody function to fight persistent virus infection.
Persistent viral infections represent one of the greatest health concerns worldwide. The proposed experiments will define a mechanism of immunosuppression during viral persistence that limits otherwise effective antibody function. Our study has important implications for the design of therapies to restore antibody activity to fight persistent viruses.