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Research Summary

Our research in the infectious diseases area focuses on understanding the mechanism of pathogen-host interaction in viral entry process and protective humoral immune response triggered upon natural infection and vaccination, then applying that knowledge to vaccine and antiviral therapeutic design.

1. Henipavirus (HNV) glycoproteins’ structure, function and protective immune recognition mechanism. HNV is a genus of negative-strand RNA viruses in the family Paramyxoviridae. Members of this expanding zoonotic viral group have caused repeated outbreaks with case fatality rate reaching 75%. The exceptional broad species tropism and various transmission routes make HNV a risk of potential future pandemics. Glycoproteins F and G are the two only spikes on the HNV surface, which coordinate the viral entry process via G glycoprotein-mediated receptor attachment followed by the F glycoprotein-mediated membrane fusion between virus and host cell. Both G and F proteins are the targets of HNV-neutralizing antibodies. Vaccine and monoclonal antibody (mAb) countermeasure development focusing on these two HNV glycoproteins are now of critical and urgent importance to prepare for potential HNV spillover events. Our structural and functional studies uncovered the functional role of G and F glycoproteins in viral entry process, and how they can be recognized by protective antibodies, which paves the way for further vaccine and therapeutic design.

Wang Z, Dang HV, Amaya M, Xu Y, Yin R, Yan L, Hickey AC, Annand EJ, Horsburgh BA, Reid PA, Smith I, Eden JS, Xu K#, Broder CC#, Veesler D#. Potent monoclonal antibody-mediated neutralization of a divergent Hendra virus variant. Proc Natl Acad Sci U S A. 2022 May 31;119(22)

Laing ED, Navaratnarajah CK, Cheliout Da Silva S, et al, Broder CC# and Xu K#. Structural and Functional Analyses Reveal Promiscuous and Species-Specific Use of Ephrin Receptors by Cedar Virus. (2019) Proc Natl Acad Sci U S A. Oct 8;116(41):20707-20715.

Xu K*, Chan YP*, Bradel-Tretheway B*, Akyol-Ataman Z*, Zhu Y*, Dutta S, Yan L, Feng Y, Wang LF, Skiniotis G, Lee B, Zhou ZH, Broder CC, Aguilar HC, Nikolov DB. Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly. (2015) PLoS Pathog. Dec 8;11(12)

Xu K, Rockx B, Xie YH, DeBuysscher BL, Fusco DL, Zhu ZY, Chan YP, Xu Y, Luu T, Cer RZ, Feldmann H, Mokashi V, Dimitrov DS, Bishop-Lilly KA, Broder CC, Nikolov DB. Crystal structure of the Hendra virus attachment G glycoprotein bound to a potent cross-reactive neutralizing human monoclonal antibody. (2013) PLoS Pathog., 9(10):e1003684. 

2. HIV vaccine research. Through structural and functional characterization of broadly HIV neutralizing antibodies, we revealed HIV fusion peptide as promising vaccine target. With antibody-guided and structure-based approach we designed fusion peptide-based HIV vaccine, and validated vaccine efficacy in mouse, guinea pig and NHP immunization studies. Jointly we isolated FP-directed broadly neutralizing antibodies (up to 59% overall breadth) from FP vaccinated NHPs and defined their developmental pathways.

Xu K*, Acharya P*, Kong R*, Cheng C*, et al, Mascola JR, Kwong PD. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. (2018) Nat Med. Jun;24(6):857-867.

Kong R*, Duan H*, Sheng Z*, Xu K*, Acharya P*, Chen X*, Cheng C*, Dingens AS*, Gorman J*, Sastry M*, Shen CH*, Zhang B*, Zhou T*, et al, Kwong PD, Mascola JR. Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization. (2019) Cell. Jul 25; 178(3): 567-584.

Kong R*, Xu K*, Zhou T*, et al, Kwong PD, Mascola JR. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. (2016) Science. May 13;352(6287):828-33.

Zhou T, Xu K. Structural Features of Broadly Neutralizing Antibodies and Rational Design of Vaccine. (2018) Adv Exp Med Biol. 1075:73-95.

3. Other infectious diseases. COVID-related: We developed and characterized a series of protective nanobodies against SARS-CoV2 and its variants and identified conserved neutralizing targets for vaccine design. Malaria-related: We revealed the mechanism of Plasmodium RIFIN-mediated immune suppression as well as Plasmodium recognition by recently discovered domain-inserted antibodies. Paramyxovirus research: We developed a tetravalent subunit of hPIV1-4 vaccine using structure-based design to stabilize the F glycoproteins in their prefusion status.

Xu J*, Xu K*, Jung S, Conte A, Lieberman J, Muecksch F, Lorenzi JCC, Park S, Schmidt F, Wang Z, Huang Y, Luo Y, Nair M, Wang P, Schulz JE, Tessarollo L, Bylund T, Chuang GY, Olia AS, Stephens T, Teng IT, Tsybovsky Y, Zhou T, Munster V, Ho DD, Hatziioannou T, Bieniasz PD, Nussenzweig MC, Kwong PD, Casellas R. Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants. (2021) Nature. Jun 7.

Xu K#, Wang Y, Shen CH, Chen Y, Zhang B, Liu K, Tsybovsky Y, Wang S, Farney SK, Gorman J, Stephens T, Verardi R, Yang Y, Zhou T, Chuang GY, Lanzavecchia A, Piccoli L, Kwong PD#. Structural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs. (2021) Nat Commun. Jul 9;12(1):4226.

Chen Y*, Xu K*, Piccoli L, Foglierini M, Tan J, Jin W, Gorman J, Tsybovsky Y, Zhang B, Traore B, Silacci-Fregni C, Daubenberger C, Crompton PD, Geiger R, Sallusto F, Kwong PD, Lanzavecchia A. Structural basis of malaria RIFIN binding by LILRB1-containing antibodies (2021) Nature Apr;592(7855):639-643.

Stewart-Jones GBE*, Chuang GY*, Xu K*, Zhou T*, Acharya P*, Tsybovsky Y*, et al, Mascola JR, Lanzavecchia A, Kwong PD. Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4. (2018) Proc Natl Acad Sci U S A. (2018) Nov 27;115(48):12265-12270.