title: Molecular insights into the inhibition of HIV-1 infection using a CD4 domain-1-specific monoclonal antibody.
abstract: An HIV-1 infection in a host cell occurs through an ordered process that involves HIV-1 attachment to the host's cellular CD4 receptor, co-receptor binding to CCR5 or CXCR4, and the subsequent fusion with the cellular membrane. The natural viral entry pathway into a host cell provides an opportunity to develop agents for the treatment of HIV-1 infections. Several engineered monoclonal antibodies specifically targeting CD4 have shown antiviral activities in clinical trials. Here, we report on an anti-CD4 mAb (15A7) that displays a unique binding specificity for domain 1 of CD4, whose epitope partially overlaps with the gp120 binding region. Moreover, 15A7 displays a much stronger binding affinity to CD4(+) cell lines after HIV infection. 15A7 is able to block and neutralize a broad range of primary HIV-1 isolates and T cell-line passage strains. Notably, the bivalent F(ab')2 form of 15A7 is more effective than the Fab form in blocking HIV-1 infection, which is further supported by molecular docking analyses. Together, these results suggest that this novel antibody may exert its antiviral activity by blocking gp120 targeting to the CD4 receptor or competing with gp120 for CD4 receptor binding and might present post-attachment neutralization activity. This antibody could provide a new candidate to efficiently block HIV-1 infection or provide new starting materials for HIV treatment, especially when HIV-1-resistant strains against the current CD4 mAb treatments have already been identified.
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Wangheng
authors.initials: W
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Chu
authors.initials: C
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.affiliation: National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
authors.forename: Jialong
authors.initials: J
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xiong
authors.affiliation: National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
authors.forename: Shuangquan
authors.initials: S
authors.lastname: Gao
authors.affiliation: National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China; National University of Singapore (Suzhou) Research Institute, Suzhou 215123, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Adam Yuan
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China. Electronic address: guying@xmu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
authors.forename: Ningshao
authors.initials: N
authors.lastname: Xia
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009500:Neutralization Tests; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120
keywords: Anti-CD4 antibody; Broad neutralization; HIV-1; Infection blocking