title: Structural and immunogenicity studies of a cleaved, stabilized envelope trimer derived from subtype A HIV-1.
abstract: SOSIP gp140 trimers represent a soluble, stabilized, proteolytically cleaved form of the HIV-1 envelope (Env) glycoproteins. SOSIP gp140 derived from a subtype A HIV-1 isolate, KNH1144, forms exceptionally stable trimers that resemble virion-associated Env in antigenicity and topology. Here, we used electron microscopy to demonstrate that KNH1144 SOSIP gp140 trimers bound three soluble CD4 molecules in a symmetrical orientation similar to that seen for native Env. We compared the immunogenicities of KNH1144 SOSIP gp140 trimers and gp120 monomers in rabbits and found that the trimers were superior at eliciting neutralizing antibodies (NAbs) to homologous virus as well as neutralization-sensitive subtype B and C viruses. The NAb specificities for SOSIP antisera mapped in part to the CD4 binding site on gp120. We also observed adjuvant-dependent induction of antibodies to the residual levels of host cell proteins (HCPs) contained in the purified Env preparations. When present, HCP antibodies enhanced pseudovirus infection. Our findings are relevant for the further development of Env-based vaccines for HIV-1.
authors: Progenics Pharmaceuticals, Inc., Tarrytown, NY 10591, United States. kkang@progenics.com
authors: Yun Kenneth
authors: YK
authors: Kang
authors: Sofija
authors: S
authors: Andjelic
authors: James M
authors: JM
authors: Binley
authors: Emma T
authors: ET
authors: Crooks
authors: Michael
authors: M
authors: Franti
authors: Sai Prasad N
authors: SP
authors: Iyer
authors: Gerald P
authors: GP
authors: Donovan
authors: Antu K
authors: AK
authors: Dey
authors: Ping
authors: P
authors: Zhu
authors: Kenneth H
authors: KH
authors: Roux
authors: Robert J
authors: RJ
authors: Durso
authors: Thomas F
authors: TF
authors: Parsons
authors: Paul J
authors: PJ
authors: Maddon
authors: John P
authors: JP
authors: Moore
authors: William C
authors: WC
authors: Olson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D009500:Neutralization Tests; D020836:Protein Structure, Quaternary; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1; C097729:gp140 envelope protein, Human immunodeficiency virus 1