title: Differential induction of anti-V3 crown antibodies with cradle- and ladle-binding modes in response to HIV-1 envelope vaccination.
abstract: The V3 loop in the HIV envelope gp120 is one of the immunogenic sites targeted by Abs. The V3 crown in particular has conserved structural elements recognized by cross-reactive neutralizing Abs, indicating its potential contribution in protection against HIV. Crystallographic analyses of anti-V3 crown mAbs in complex with the V3 peptides have revealed that these mAbs recognize the conserved sites on the V3 crown via two distinct strategies: a cradle-binding mode (V3C) and a ladle-binding (V3L) mode. However, almost all of the anti-V3 crown mAbs studied in the past were isolated from chronically HIV-infected individuals. The extents to which the two types of anti-V3 crown Abs are generated by vaccination are unknown. This study analyzed the prevalence of V3C-type and V3L-type Ab responses in HIV-infected individuals and in HIV envelope-immunized humans and animals using peptide mimotopes that distinguish the two Ab types. The results show that both V3L-type and V3C-type Abs were generated by the vast majority of chronically HIV-infected humans, although the V3L-type were more prevalent. In contrast, only one of the two V3 Ab types was elicited in vaccinated humans or animal models, irrespective of HIV-1 envelope clades, envelope constructs (oligomeric or monomeric), and protocols (DNA plus protein or protein alone) used for vaccinations. The V3C-type Abs were produced by vaccinated humans, macaques, and rabbits, whereas the V3L-type Abs were made by mice. The V3C-type and V3L-type Abs generated by the vaccinations were able to mediate virus neutralization. These data indicate the restricted repertoires and the species-specific differences in the functional V3-specific Ab responses induced by the HIV envelope vaccines. The study implies the need for improving immunogen designs and vaccination strategies to broaden the diversity of Abs in order to target the different conserved epitopes in the V3 loop and, by extension, in the entire HIV envelope.
authors.affiliation: The Sackler Institute of Graduate Biomedical Sciences, NYU School of Medicine, New York, NY 10016, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Preetha
authors.initials: P
authors.lastname: Balasubramanian
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters VA Medical Center, Bronx, NY 10468, USA.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Itri
authors.affiliation: University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.affiliation: University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
authors.affiliation: Global Solutions for Infectious Diseases, South San Francisco, CA, USA.
authors.forename: Faruk
authors.initials: F
authors.lastname: Sinangil
authors.affiliation: Global Solutions for Infectious Diseases, South San Francisco, CA, USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Higgins
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Liuzhe
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Phillipe
authors.initials: P
authors.lastname: Nyambi
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.affiliation: Molsoft LLC, 3366 N Torrey Pines Ct., La Jolla, CA 92037, USA.
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
authors.affiliation: Department of Environment Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Nadas
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters VA Medical Center, Bronx, NY 10468, USA. Electronic address: catarina.hioe@mssm.edu.
authors.forename: Catarina E
authors.initials: CE
authors.lastname: Hioe
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008251:Macaca; D051379:Mice; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: Antibodies; HIV; HIV envelope; Mimotopes; V3