Journal Article

mAb therapy controls CNS‐resident lyssavirus infection via a CD4 T cell‐dependent mechanism

Mandal, Pratyusha, Clouse, Caitlyn, Ahmed, Anwar E, Broder, Christopher C, Coggins, Si'Ana A, Mastraccio, Kate E, Rader, Madeline, Laing, Eric D, Smith, Ina L, Schaefer, Brian C, Yan, Lianying, Vu, Bang K, Weir, Dawn L, Ho, Trung, Feasley, Austin, Hussain, Imran, Huaman, Celeste, Markotter, Wanda

2023

Overview

Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre‐symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti‐lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11‐dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell‐dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ‐binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization‐independent T cell‐mediated effects, even against an established CNS infection by a lethal neurotropic virus. Synopsis Rabies is a fatal viral disease of humans, with uniform mortality once central nervous system (CNS) invasion occurs and symptoms appear. This study demonstrates that a single‐dose monoclonal (mAb) therapy can yield a functional cure for rabies, even after robust CNS replication. Peripheral administration of mAb F11 reduces CNS viral replication and prevents mortality, following infection of mice with a lethal dose of either Australian bat lyssavirus (ABLV) or rabies virus (RABV). Therapeutic efficacy of F11, a human IgG1, requires a functional antibody Fc region, implicating the mechanistic involvement of immune cells bearing FcRγ. F11 efficacy requires an intact host adaptive immune response, particularly CD4 T cells. Administration of F11 alters both the proportions and phenotypes of immune cells in the brains of ABLV‐infected animals. Virus persists chronically at a low level in the brains of F11‐treated animals, but animals remain free of disease signs. Graphical Abstract Rabies is a fatal viral disease of humans, with uniform mortality once central nervous system (CNS) invasion occurs and symptoms appear. This study demonstrates that a single‐dose monoclonal (mAb) therapy can yield a functional cure for rabies, even after robust CNS replication.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Adaptive immunity / Animals / Antibodies, Monoclonal - therapeutic use / Australian bat lyssavirus / Bats / Bioluminescence / Brain / CD4 antigen / CD4-Positive T-Lymphocytes / Central nervous system / Central Nervous System Infections / Chiroptera / Disease prevention / EMBO19 / EMBO23 / EMBO27 / Fc function / Humans / Immunotherapy / Infections / Lethal dose / Lymphocytes / Lymphocytes T / Lyssavirus / Monoclonal antibodies / monoclonal antibody / Mortality / Rabies / Rabies - prevention & control / Rabies virus / Replication initiation / Rhabdoviridae Infections - drug therapy / Rhabdoviridae Infections - prevention & control / Vaccines / Viral infections / Viruses