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

Simon Beddows, Michael Franti, Antu K. Dey, Marc Kirschner, Sai Prasad N Iyer, Danielle C. Fisch, Thomas Ketas, Eloisa Yuste, Ronald Charles Desrosiers, Per Johan Klasse, Paul J. Maddon, William C. Olson, John P. Moore

Research output: Contribution to journalArticle

82 Citations (Scopus)

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-1JR-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 (gp140UNC), 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-1JR-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-1JR-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.

Original languageEnglish (US)
Pages (from-to)329-340
Number of pages12
JournalVirology
Volume360
Issue number2
DOIs
StatePublished - Apr 10 2007
Externally publishedYes

Fingerprint

Neutralizing Antibodies
Disulfides
HIV-1
Rabbits
Membrane Glycoproteins
HIV
Vaccines
Virus Attachment
Proteins
DNA
Mutagenesis
Epitopes
Immunization
Glycoproteins
Antigens
GP 140
Antibodies
Infection

Keywords

  • Cleavage
  • Envelope
  • HIV-1
  • Immunogen
  • Neutralizing antibodies
  • Trimers

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

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. / Beddows, Simon; Franti, Michael; Dey, Antu K.; Kirschner, Marc; Iyer, Sai Prasad N; Fisch, Danielle C.; Ketas, Thomas; Yuste, Eloisa; Desrosiers, Ronald Charles; Klasse, Per Johan; Maddon, Paul J.; Olson, William C.; Moore, John P.

In: Virology, Vol. 360, No. 2, 10.04.2007, p. 329-340.

Research output: Contribution to journalArticle

Beddows, Simon ; Franti, Michael ; Dey, Antu K. ; Kirschner, Marc ; Iyer, Sai Prasad N ; Fisch, Danielle C. ; Ketas, Thomas ; Yuste, Eloisa ; Desrosiers, Ronald Charles ; Klasse, Per Johan ; Maddon, Paul J. ; Olson, William C. ; Moore, John P. / 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. In: Virology. 2007 ; Vol. 360, No. 2. pp. 329-340.
@article{202d826c613a4101b419295f04373cc6,
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-1JR-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 (gp140UNC), 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-1JR-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-1JR-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.",
keywords = "Cleavage, Envelope, HIV-1, Immunogen, Neutralizing antibodies, Trimers",
author = "Simon Beddows and Michael Franti and Dey, {Antu K.} and Marc Kirschner and Iyer, {Sai Prasad N} and Fisch, {Danielle C.} and Thomas Ketas and Eloisa Yuste and Desrosiers, {Ronald Charles} and Klasse, {Per Johan} and Maddon, {Paul J.} and Olson, {William C.} and Moore, {John P.}",
year = "2007",
month = "4",
day = "10",
doi = "10.1016/j.virol.2006.10.032",
language = "English (US)",
volume = "360",
pages = "329--340",
journal = "Virology",
issn = "0042-6822",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - 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

AU - Beddows, Simon

AU - Franti, Michael

AU - Dey, Antu K.

AU - Kirschner, Marc

AU - Iyer, Sai Prasad N

AU - Fisch, Danielle C.

AU - Ketas, Thomas

AU - Yuste, Eloisa

AU - Desrosiers, Ronald Charles

AU - Klasse, Per Johan

AU - Maddon, Paul J.

AU - Olson, William C.

AU - Moore, John P.

PY - 2007/4/10

Y1 - 2007/4/10

N2 - 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-1JR-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 (gp140UNC), 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-1JR-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-1JR-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.

AB - 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-1JR-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 (gp140UNC), 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-1JR-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-1JR-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.

KW - Cleavage

KW - Envelope

KW - HIV-1

KW - Immunogen

KW - Neutralizing antibodies

KW - Trimers

UR - http://www.scopus.com/inward/record.url?scp=33947590277&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947590277&partnerID=8YFLogxK

U2 - 10.1016/j.virol.2006.10.032

DO - 10.1016/j.virol.2006.10.032

M3 - Article

C2 - 17126869

AN - SCOPUS:33947590277

VL - 360

SP - 329

EP - 340

JO - Virology

JF - Virology

SN - 0042-6822

IS - 2

ER -