title: Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits.
abstract: The V1V2 region of HIV-1 gp120 harbors a major vulnerable site targeted by a group of broadly neutralizing monoclonal antibodies (MAbs) such as PG9 through strand-strand recognition. However, this epitope region is structurally polymorphic as it can also form a helical conformation recognized by RV144 vaccine-induced MAb CH58. This structural polymorphism is a potential mechanism for masking the V1V2 vulnerable site. Designing immunogens that can induce conformation-specific antibody (Ab) responses may lead to vaccines targeting this vulnerable site. We designed a panel of immunogens engrafting the V1V2 domain into trimeric and pentameric scaffolds in structurally constrained conformations. We also fused V1V2 to an Fc fragment to mimic the unconstrained V1V2 conformation. We tested these V1V2-scaffold proteins for immunogenicity in rabbits and assessed the responses by enzyme-linked immunosorbent assay (ELISA) and competition assays. Our V1V2 immunogens induced distinct conformation-specific Ab responses. Abs induced by structurally unconstrained immunogens reacted preferentially with unconstrained V1V2 antigens, suggesting recognition of the helical configuration, while Abs induced by the structurally constrained immunogens reacted preferentially with constrained V1V2 antigens, suggesting recognition of the β-strand conformation. The Ab responses induced by the structurally constrained immunogens were more broadly reactive and had higher titers than those induced by the structurally unconstrained immunogens. Our results demonstrate that immunogens presenting the different structural conformations of the gp120 V1V2 vulnerable site can be designed and that these immunogens induce distinct Ab responses with epitope conformation specificity. Therefore, these structurally constrained V1V2 immunogens are vaccine prototypes targeting the V1V2 domain of the HIV-1 envelope.
  
  
  OBJECTIVE
  The correlates analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the V1V2 region of HIV-1 gp120 was responsible for the modest protection observed in the trial. In addition, V1V2 harbors one of the key vulnerable sites of HIV-1 Env recognized by a family of broadly neutralizing MAbs such as PG9. Thus, V1V2 is a key target for vaccine development. However, this vulnerable site is structurally polymorphic, and designing immunogens that present different conformations is crucial for targeting this site. We show here that such immunogens can be designed and that they induced conformation-specific antibody responses in rabbits. Our immunogens are therefore prototypes of vaccine candidates targeting the V1V2 region of HIV-1 Env.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Xunqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Molsoft, LLC, San Diego, California, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Totrov
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Sampson
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, USA.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Susan
authors.identifier: http://orcid.org/0000-0002-0750-2666
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA xiangpeng.kong@med.nyu.edu.
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D057134:Antibodies, Neutralizing / Q000096:biosynthesis; D003429:Cross Reactions; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D015870:Gene Expression; D015483:HIV Antibodies / Q000096:biosynthesis*; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D000071497:Immunogenicity, Vaccine; D008958:Models, Molecular; D010449:Peptide Mapping; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011993:Recombinant Fusion Proteins