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

被引:86
|
作者
Beddows, Simon
Franti, Michael
Dey, Antu K.
Kirschner, Marc
Iyer, Sal Prasad N.
Fisch, Danielle C.
Ketas, Thomas
Yuste, Eloisa
Desrosiers, Ronald C.
Klasse, Per Johan
Maddon, Paul J.
Olson, William C.
Moore, John P.
机构
[1] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA
[2] Progen Pharmaceut Inc, New York, NY 10591 USA
[3] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, New England Primate Res Ctr, Southborough, MA 01772 USA
关键词
HIV-1; envelope; cleavage; trimers; immunogen; neutralizing antibodies;
D O I
10.1016/j.virol.2006.10.032
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The human immunodeficiency virus type I (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 afternative 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 gp 120 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 (gp 140(UNC)), the other contains an intramolecular disulfide bond to stabilize the cleaved gp 120 and gp41 moieties (SOSIP.R6 gp 140). Among the three immunogens, SOSIP.R6 gp, 140 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. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:329 / 340
页数:12
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