Control of established, CNS-resident lyssavirus infection by an adaptive immune response stimulated by single-dose monoclonal antibody therapy

Abstract

Abstract Rabies virus and related lyssaviruses cause uniformly fatal disease, once the infection progresses to the central nervous system. Current lyssavirus immunotherapies are directed toward peripheral neutralization of virus to prevent CNS infection during the pre-symptomatic stage of disease. In this study, using an anti-lyssavirus human monoclonal antibody (mAb), F11, we evaluated the efficacy of immunotherapy on established lyssavirus infections in mice. Remarkably, using luminescence-based longitudinal tracing of virus infection in a mouse model of lethal disease, we found that a single dose of F11 reverses clinical signs of disease and protects animals from lethality following lyssavirus infection, even when administered after initiation of virus replication in the CNS. Investigation of the mechanisms of F11 efficacy revealed that F11-dependent neutralization is insufficient to protect animals from mortality. Control of infection requires an intact adaptive immune response, particularly CD4 T cells. Additionally, in vivo analysis of the F11-N297G mutant, which has defective FcRγ binding, showed a transiently increased viral load and increased morbidity when compared to F11 treated mice. Despite long-term survival and absence of clinical signs of disease in F11-treated animals, we found that lyssavirus infection persists chronically, concomitant with elevated expression of cellular immune response genes. These findings demonstrate that single-dose mAb therapy can stimulate an adaptive, T cell-dependent response that is durable and highly effective against an established CNS infection by a lethal neurotropic virus. Supported by grants from the National Institute of Health (U01GM109887, R01AI125552), and a USU Program Project Grant (MIC-732515) and a USU Center for Global Health Engagement grant (HU00011920118)