title: Single N277A substitution in C2 of simian immunodeficiency virus envelope influences vaccine-elicited CD4i neutralizing and anti-V2 antibody responses.
abstract: An effective HIV vaccine remains elusive, and immunogens capable of eliciting protective host humoral immunity have not yet been identified. Although HIV/SIV infections result in the abundant production of CD4-induced (CD4i) antibodies (Abs), these Abs are not protective due to steric restrictions following gp120 binding to CD4 on target cells. Here we report that both DNA- and vaccinia-based vaccines encoding SIVmac239gp160 readily elicited high levels of CD4i Abs in experimental animals. We identified a highly conserved N-linked glycosylation site N277 in the C2 region which strongly affected the immunogenicity of the CD4i Ab domain. Moreover, a single N277A substitution significantly enhanced the immunogenicity of the V2 domain yielding higher titers and frequency of anti-V2 Ab responses as determined by ELISA and yeast antigen display mapping, respectively. Importantly, immune sera elicited by the N277A-mutated gp160 exhibited elevated antibody-dependent cellular cytotoxicity (ADCC) activity. ADCC activity correlated positively with the anti-V2 Ab titer yet, inversely with CD4i Ab titer. Thus, we identified a determinant of the CD4i domain that might affect vaccine-elicited anti-V2 Ab and ADCC responses to SIVmac239. Our findings may have implications for design of immunogens to direct B cell recognition in the development of an Ab-based HIV vaccine.
authors.affiliation: HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Lab of Emerging Infectious Diseases and Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, China; AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Xian
authors.initials: X
authors.lastname: Tang
authors.affiliation: AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Lab of Emerging Infectious Diseases and Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Caijun
authors.initials: C
authors.lastname: Sun
authors.affiliation: AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Comprehensive AIDS Research Center and Research Center for Public Health, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Zuo
authors.affiliation: HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Lab of Emerging Infectious Diseases and Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Comprehensive AIDS Research Center and Research Center for Public Health, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Lab of Emerging Infectious Diseases and Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, China; AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: zchenai@hku.hk.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000917:Antibody Formation; D000920:Antibody-Dependent Cell Cytotoxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology*; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D050505:Mutant Proteins; D018449:SAIDS Vaccines; D014759:Viral Envelope Proteins
keywords: ADCC; CD4-induced; HIV; Mutagenesis; V2; Vaccine