Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.
Highlights
Chikungunya virus (CHIKV) infection causes a severe febrile illness in humans that is characterized by a debilitating polyarthritis, which can persist for months and cause significant morbidity [1,2]
We immunized Irf72/2 rather than wild type (WT) mice, as CHIKV replicated to higher titers, induced stronger neutralizing antibody responses, yet did not cause lethal infection in these innate immune-deficient animals ([31], and data not shown)
Neutralizing activity To assess the inhibitory potential of our anti-CHIKV monoclonal antibodies (MAbs) against the homologous CHIKV-LR and representative strains from the Asian and West African genotypes (RSU1 and IbH35 respectively), we performed focus reduction neutralization tests (FRNTs) on Vero cells
Summary
Chikungunya virus (CHIKV) infection causes a severe febrile illness in humans that is characterized by a debilitating polyarthritis, which can persist for months and cause significant morbidity [1,2]. The mature virion is comprised of three structural proteins: a nucleocapsid protein and two glycoproteins, E1 and E2, where E2 functions in attachment to cells and E1 participates in virus fusion. Each 700 A CHIKV virion contains 240 copies of the envelope and capsid proteins, which are arranged in T = 4 quasiicosahedral symmetry. E1-E2 heterodimers assemble into 80 trimeric spikes on the virus surface [9]. X-ray crystallographic structures of the precursor pE3-E2-E1, mature E2-E1, and E1 proteins [10–13] have elucidated the architecture of the glycoprotein shell. Domain I (DI) is located between DII and DIII, the latter of which adopts an immunoglobulin-like fold. E2 localizes to a long, thin leaf-like structure on the top of the spike. The mature E2 protein contains three domains with immunoglobulin-like folds: the N-terminal domain A, located at the center; Author Summary
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