title: A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120.
abstract: The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1(JR-FL). Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140(UNC)), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1(JR-FL). All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1(JR-FL) were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Beddows
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.forename: Marc
authors.initials: M
authors.lastname: Kirschner
authors.forename: Sai Prasad N
authors.initials: SP
authors.lastname: Iyer
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Fisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Ketas
authors.forename: Eloisa
authors.initials: E
authors.lastname: Yuste
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Desrosiers
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Maddon
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D018604:Epitope Mapping; D015686:Gene Products, env / Q000737:chemistry / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007117:Immunization, Secondary; D023421:Models, Animal; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D019444:Vaccines, DNA / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1