title: Elicitation of neutralizing antibodies directed against CD4-induced epitope(s) using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein.
abstract: The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M) and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application.
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.forename: Brian
authors.initials: B
authors.lastname: Burke
authors.forename: Yide
authors.initials: Y
authors.lastname: Sun
authors.forename: Klara
authors.initials: K
authors.lastname: Sirokman
authors.forename: Avishek
authors.initials: A
authors.lastname: Nandi
authors.forename: Karin
authors.initials: K
authors.lastname: Hartog
authors.forename: Ying
authors.initials: Y
authors.lastname: Lian
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Geonnotti
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.forename: Grégoire
authors.initials: G
authors.lastname: Martin
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfi
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Srivastava
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
mesh_terms: D016915:AIDS Vaccines / Q000138:chemical synthesis / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism*; D000917:Antibody Formation / Q000187:drug effects; D032701:Biomimetics; D015704:CD4 Antigens / Q000276:immunology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D007114:Immunization; D009500:Neutralization Tests; D011817:Rabbits; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D000939:Epitopes; D015483:HIV Antibodies; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus