Structural and Functional Inhibition of CHIKV by CHK-124 and CHK-263mAbs

Souradip Mallick, National Institute of Technology, Rourkela

Chikungunya fever is a self-remitting viral illness that is common in tropical countries like Africa and Southeast Asia caused by the Chikungunya virus (CHIKV) (Genus- alphavirus, Family-Togaviridae), single-stranded positive-sense RNA enveloped virus, transmitted to humans by infected Aedes aegypti and Aedes albopictus mosquitoes. International travel is one of the risk factors for the rapid global spread of this disease. CHIKV infection has many signs and symptoms like fever and severe joint pain including muscle pain, joint swelling, headache, nausea, fatigue as well as both acute and chronic arthritis.

The CHIKV RNA genome is packed within an icosahedral nuclear capsid core made up of host-derived lipid bilayer. The mature CHIKV particle have E1-E2 heterodimer spike protein attached on that lipid bilayer membrane.E1 spike protein has three domains: E1-DI; E1-DII and E1-DIII; and E2 spike protein has E2-DA, E2-DB, and E2-DC.E1-DII mediates endosomal membrane fusion and therefore the groove is formed by E2-DA and E2-DB which shields the fusion loop of E1 protein from premature membrane fusion at neutral pH. Mxra8 is an alphavirus receptor which recognizes an epitope spanning both the E1 and E2 proteins thus bind across different E1-E2 heterodimers on the CHIKV surface.

Still, now there is no CHIKV vaccine or therapeutics. But there are two CHIKV monoclonal antibodies, CHK-124 and CHK-263, which inhibit CHIKV infection cycle in vitro and in vivo by following ways

• Neutralizing CHIKV infection in vivo
• Blocking Multiple Pathways in the Virus Infection Cycle

The mouse monoclonal antibodies (mAbs) CHK-124 and CHK-263 exhibit intense neutralizing activity in vitro using a focus reduction neutralization test using a wild type C57BL/6 mouse model of CHIKV arthritis. The inhibitory activities of CHK-124 were reduced when bivalency of IgG was abolished by the use of Fab fragments compared to CHK-263. Antibodies were added either before or after virus attachment to prove that CHK-124 and CHK-263 IgGs are highly neutralizing in both pre- and post-attachment neutralization assays, whereas their Fabs have weaker activities. 

Thus CHK-124 aggregates virus particles and blocks attachment. Also, fusion with endosomes takes place due to antibody-induced virus aggregation. CHK-263 blocks virus attachment and fusion thus neutralize CHIKV infection. Lastly to determine the structural basis of neutralization, cryogenic electron microscopy reconstructions of Fab. These results provide structural insight into how to neutralizing antibody engagement of CHIKV by inhibiting different stages of the viral life cycle. This observation shows light on therapeutic designing and vaccine development.

Also read: Is it possible to detect COVID 19 under 15 minutes?

REFERENCE- Qun Fei Zhou, Julie M. Fox, James T. Earnest, Thiam-Seng Ng, Arthur S. Kim, Guntur Fibriansah, Victor A. Kostyuchenko, Jian Shi, Bo Shu, Michael S. Diamond, and Shee-Mei Lok- “Structural basis of Chikungunya virus inhibition by monoclonal antibodies”, PNAS,   October 21, 2020; https://doi.org/10.1073/pnas.2008051117

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