title: Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response.
abstract: Strong antibody (Ab) responses against V1V2 epitopes of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope (Env) correlated with reduced infection rates in studies of HIV, simian-human immunodeficiency virus (SHIV), and simian immunodeficiency virus (SIV). In order to focus the Ab response on V1V2, we used six V1V2 sequences and nine scaffold proteins to construct immunogens which were tested using various immunization regimens for their ability to induce cross-reactive and biologically active V2 Abs in rabbits. A prime/boost immunization strategy was employed using gp120 DNA and various V1V2-scaffold proteins. The rabbit polyclonal Ab responses (i) were successfully focused on the V1V2 region, with weak or only transient responses to other Env epitopes, (ii) displayed broad cross-reactive binding activity with gp120s and the V1V2 regions of diverse strains from clades B, C, and E, (iii) included V2 Abs with specificities similar to those found in HIV-infected individuals, and (iv) remained detectable ≥1 year after the last boosting dose. Importantly, sera from rabbits receiving V1V2-scaffold immunogens displayed Ab-dependent cellular phagocytosis whereas sera from rabbits receiving only gp120 did not. The results represent the first fully successful example of reverse vaccinology in the HIV vaccine field with rationally designed epitope scaffold immunogens inducing Abs that recapitulate the epitope specificity and biologic activity of the human monoclonal Abs from which the immunogens were designed. Moreover, this is the first immunogenicity study using epitope-targeting, rationally designed vaccine constructs that induced an Fc-mediated activity associated with protection from infection with HIV, SIV, and SHIV.
  
  
  OBJECTIVE
  Novel immunogens were designed to focus the antibody response of rabbits on the V1V2 epitopes of HIV-1 gp120 since such antibodies were associated with reduced infection rates of HIV, SIV, and SHIV. The vaccine-induced antibodies were broadly cross-reactive with the V1V2 regions of HIV subtypes B, C and E and, importantly, facilitated Fc-mediated phagocytosis, an activity not induced upon immunization of rabbits with gp120. This is the first immunogenicity study of vaccine constructs that focuses the antibody response on V1V2 and induces V2-specific antibodies with the ability to mediate phagocytosis, an activity that has been associated with protection from infection with HIV, SIV, and SHIV.
authors.affiliation: Departments of Medicine (Division of Infectious Diseases) and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Susan.Zolla-Pazner@mssm.edu.
authors.forename: Susan
authors.identifier: http://orcid.org/0000-0002-0750-2666
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Departments of Medicine (Division of Infectious Diseases) and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Powell
authors.affiliation: Departments of Medicine (Division of Infectious Diseases) and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Yahyaei
authors.affiliation: Department of Biochemistry and Office of Science and Research, New York University School of Medicine, New York, New York, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.affiliation: Department of Biochemistry and Office of Science and Research, New York University School of Medicine, New York, New York, USA.
authors.forename: Xunqing
authors.initials: X
authors.lastname: Jiang
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 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: Departments of Medicine (Division of Infectious Diseases) and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Chitra
authors.initials: C
authors.lastname: Upadhyay
authors.affiliation: Departments of Medicine (Division of Infectious Diseases) and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Catarina E
authors.initials: CE
authors.lastname: Hioe
authors.affiliation: Molsoft, LLC, San Diego, California, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Totrov
authors.affiliation: Department of Biochemistry and Office of Science and Research, New York University School of Medicine, New York, New York, USA.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Kong
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; 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; D017433:Protein Structure, Secondary; D011817:Rabbits; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins