title: A multivalent clade C HIV-1 Env trimer cocktail elicits a higher magnitude of neutralizing antibodies than any individual component.
abstract: The sequence diversity of human immunodeficiency virus type 1 (HIV-1) presents a formidable challenge to the generation of an HIV-1 vaccine. One strategy to address such sequence diversity and to improve the magnitude of neutralizing antibodies (NAbs) is to utilize multivalent mixtures of HIV-1 envelope (Env) immunogens. Here we report the generation and characterization of three novel, acute clade C HIV-1 Env gp140 trimers (459C, 405C, and 939C), each with unique antigenic properties. Among the single trimers tested, 459C elicited the most potent NAb responses in vaccinated guinea pigs. We evaluated the immunogenicity of various mixtures of clade C Env trimers and found that a quadrivalent cocktail of clade C trimers elicited a greater magnitude of NAbs against a panel of tier 1A and 1B viruses than any single clade C trimer alone, demonstrating that the mixture had an advantage over all individual components of the cocktail. These data suggest that vaccination with a mixture of clade C Env trimers represents a promising strategy to augment vaccine-elicited NAb responses.
  
  
  OBJECTIVE
  It is currently not known how to generate potent NAbs to the diverse circulating HIV-1 Envs by vaccination. One strategy to address this diversity is to utilize mixtures of different soluble HIV-1 envelope proteins. In this study, we generated and characterized three distinct, novel, acute clade C soluble trimers. We vaccinated guinea pigs with single trimers as well as mixtures of trimers, and we found that a mixture of four trimers elicited a greater magnitude of NAbs than any single trimer within the mixture. The results of this study suggest that further development of Env trimer cocktails is warranted.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Bricault
authors.affiliation: Division of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Kovacs
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Nkolola
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, and the New Mexico Consortium, Los Alamos, New Mexico, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Yusim
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, and the New Mexico Consortium, Los Alamos, New Mexico, USA.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shields
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Perry
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Lavine
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Seattle Biomedical Research Institute, and University of Washington, Department of Global Health, Seattle, Washington, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Ellingson-Strouss
authors.affiliation: Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town, Cape Town, South Africa.
authors.forename: Cecelia
authors.initials: C
authors.lastname: Rademeyer
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and South African Medical Research Council, Cape Town, South Africa.
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gray
authors.affiliation: Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town, Cape Town, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, and the New Mexico Consortium, Los Alamos, New Mexico, USA.
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.affiliation: Division of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA dbarouch@bidmc.harvard.edu.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D005260:Female; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood*; D015497:HIV-1 / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus