Therapeutic clearance of the virally infected nervous system via noncytopathic T cell interactions with resident myeloid cells (VAC6P.945)

Abstract

Abstract The goal of anti-viral therapy is to promote pathogen clearance without causing tissue injury. Therapeutic administration of anti-viral T cells (adoptive immunotherapy) has shown promise in clinical studies for the treatment of CMV, EBV, and adenovirus. Our laboratory models adoptive immunotherapy by transferring anti-viral memory T cells into mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV). Here we demonstrate that brain-resident myeloid cells (microglia), in addition to neurons, are persistently infected with LCMV in carrier mice. Therapeutic memory T cells can completely purge virus from persistently infected microglia and neurons without causing blood brain barrier breakdown or cellular injury. This is accomplished through a tailored release of chemoattractants that recruit adaptive immune cells, but few pathogenic innate immune cells. In addition, memory T cells enlist the support of nearly all microglia by converting them into CD11c-expressing antigen-presenting cells (APCs). We observed similarly converted myeloid cells in the brains of humans infected with JC virus and HIV-1. Using two-photon microscopy, we revealed that during clearance of the LCMV-infected brain anti-viral CD8 T cells form stable, noncytopathic interactions with CD11c+ microglia, whereas CD4 T cells interact transiently. These data demonstrate that brain-resident APCs can thwart the cytolytic functions of anti-viral T cells while allowing viral clearance.