Mechanism of neutralization associated with the E protein of Zika Virus: EDE1 antibodies and LALA variants
Introduction. Zika Virus (ZIKV) is a flavivirus spread by Aedes mosquitoes and transmitted sexually and trans-placentally.3 First discovered in 1947 in Uganda, the recent ZIKV epidemic began in Brazil in 2015.3 Beyond flu-like symptoms, ZIKV has been linked to microcephaly and Guillian-Barre’ syndrome.1 Treatment is presently supportive and preventative, but current research is exploring specific antibodies including EDE1 C8 and C10 that bind and neutralize the E protein of ZIKV.4 The process of cell entry and mechanism of neutralization related to the E protein is thought to distinguish ZIKV from other flaviviruses and is vital to the development of future therapeutic strategies.2 Methods. In the studies, mice were utilized as animal models to test the ZIKV E protein interaction with specific antibodies. Monoclonal antibodies were screened with bilayer interferometry for neutralization of ZIKV and cross-neutralization of other flaviviruses.4 Interferon knockout mice were treated with antibodies and neutralization outcomes were analyzed using crystallization and X-ray structures, pH adjustments with Cryo-EM, and antigenic cartography.4-6 Results. EDE1 antibodies like C8 and C10 more strongly neutralized ZIKV than EDE2 antibodies like B7 and A11.4 Interaction with EDE1 antibodies required an E dimer to bind to the central ß-strand, which is highly conserved in flaviviruses. EDE1 antibodies locked the entire viral surface and the E protein raft to prevent structural rearrangement required for fusion of ZIKV with the membrane.4,6 The EDE1 treated mice all survived, mostly exhibited no signs of illness, and gained more weight than ZIKV infected mice.5 Additionally, LALA variants increased therapeutic antibody safety by eliminating antibody-dependent enhancement.6 Conclusions. ZIKV and flaviviruses like DENV have geographical overlap and close to 60% similarity in sequence homology.5 Moreover, DENV has multiple drugs in late phases of clinical trials that could be cross-protective against ZIKV.5 The success of the ZIKV neutralizing antibodies EDE1 C8 and C10 in vitro and in vivo is a first step to thwarting ZIKV complications during pregnancy.5 Since fusion is a fundamental step in ZIKV infection, the EDE1 antibodies, especially LALA variants, could be great therapeutic candidates for ZIKV by blocking structural rearrangements of fusion.6 Emphasis on LALA mutated EDE1 antibodies offers promise for development of therapeutics for ZIKV and presents the potential for a universal vaccine encompassing all the flaviviruses. Most importantly, these LALA variant antibodies may offer immediate advantageous immune prophylaxis in pregnant women at risk of contracting ZIKV.4
- Duca LM, Beckham JD, Tyler KL, Pastula DM. Zika Virus Disease and Associated Neurologic Complications. Current Infectious Disease Reports. 2017;19(1): 1-8.
- Hasan SS, Miller A, Sapparapu G, et al. A human antibody against Zika virus crosslinks the E protein to prevent infection. Nature Communications. 2017;8:14722-14730.
- Shuaib W, Stanazai H, Abazid AG, Mattar AA. Re-Emergence of Zika Virus: A Review on Pathogenesis, Clinical Manifestations, Diagnosis, Treatment, and Prevention. Am J Med. 2016;129(8):879.e7-879.e12.
- Barba-Spaeth G, Dejnirattisai W, Rouvinski A, et al. Structural basis of potent Zika–dengue virus antibody cross-neutralization. Nature. 2016;539(7628):314-334.
- Swanstrom JA, Plante JA, Plante KS, et al. Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus. mBio. 2016;7(4).
- Zhang S, Kostyuchenko VA, Ng T-S, et al. Neutralization mechanism of a highly potent antibody against Zika virus. Nature Communications. 2016;7:13679-13686.