Abstract:
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 antilyssavirus
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 FcRc-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.
