title: Identification of Non-HIV Immunogens That Bind to Germline b12 Predecessors and Prime for Elicitation of Cross-clade Neutralizing HIV-1 Antibodies.
abstract: A fundamental challenge for developing an effective and safe HIV-1 vaccine is to identify vaccine immunogens that can initiate and maintain immune responses leading to elicitation of broadly neutralizing HIV-1 antibodies (bnAbs) through complex maturation pathways. We have previously found that HIV-1 envelope glycoproteins (Env) lack measurable binding to putative germline predecessors of known bnAbs and proposed to search for non-HIV immunogens that could initiate their somatic maturation. Using bnAb b12 as a model bnAb and yeast display technology, we isolated five (poly)peptides from plant leaves, insects, E. coli strains, and sea water microbes that bind to b12 putative germline and intermediate antibodies. Rabbit immunization with the (poly)peptides alone induced high titers of cross-reactive antibodies that neutralized HIV-1 isolates SF162 and JRFL. Priming rabbits with the (poly)peptides followed by boosts with trimeric gp140SF162 and then resurfaced Env (RSC3) induced antibodies that competed with mature b12 and neutralized tier 1 and 2 viruses from clade B, C and E, while control rabbits without (poly)peptide priming induced antibodies that did not compete with mature b12 and neutralized fewer isolates. The degree of competition with mature b12 for binding to gp140SF162 correlated with the neutralizing activity of the rabbit IgG. Reversing the order of the two boosting immunogens significantly affected the binding profile and neutralization potency of the rabbit IgG. Our study is the first to provide evidence that appears to support the concept that non-HIV immunogens may initiate immune responses leading to elicitation of cross-clade neutralizing antibodies.
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Liu
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yuan
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Laboratory Animals, Zhejiang Academy of Medical Sciences, Zhejiang, China.
authors.forename: Li-Qing
authors.initials: LQ
authors.lastname: Chen
authors.affiliation: Center of Laboratory Animals, Zhejiang Academy of Medical Sciences, Zhejiang, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lou
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Center of Laboratory Animals, Zhejiang Academy of Medical Sciences, Zhejiang, China.
authors.forename: Huazhong
authors.initials: H
authors.lastname: Ying
authors.affiliation: Institutes of Biomedical Sciences, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Protein Interactions group, Laboratory of Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China; Liver Disease Institute, Shenzhen Third People's Hospital, Shenzhen, 518112, China.
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D016384:Consensus Sequence; D003429:Cross Reactions / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005854:Germ Cells / Q000378:metabolism*; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D008251:Macaca / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D011817:Rabbits
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G; D010455:Peptides