title: Stabilization of HIV-1 envelope in the CD4-bound conformation through specific cross-linking of a CD4 mimetic.
abstract: CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVico, A., Fouts, T., Lewis, G. K., Gallo, R. C., Godfrey, K., Charurat, M., Harris, I., Galmin, L., and Pal, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 17477-17482). Because the inclusion of CD4 in a vaccine formulation should be avoided, due to potential autoimmune reactions, we engineered small sized CD4 mimetics (miniCD4s) that are poorly immunogenic and do not induce anti-CD4 antibodies. We made covalent complexes between such an engineered miniCD4 and gp120 or gp140, through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5. In addition, they elicit CD4i antibody responses in rabbits and therefore represent potential vaccine candidates that mimic an important HIV fusion intermediate, without autoimmune hazard.
authors.affiliation: Commissariat à l'Energie Atomique, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette F-91191, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Martin
authors.forename: Brian
authors.initials: B
authors.lastname: Burke
authors.forename: Robert
authors.initials: R
authors.lastname: Thaï
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.forename: Olivier
authors.initials: O
authors.lastname: Combes
authors.forename: Oscar H P
authors.initials: OH
authors.lastname: Ramos
authors.forename: Bernadette
authors.initials: B
authors.lastname: Heyd
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Geonnotti
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.forename: Ying
authors.initials: Y
authors.lastname: Lian
authors.forename: Yide
authors.initials: Y
authors.lastname: Sun
authors.forename: Toufik
authors.initials: T
authors.lastname: Abache
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.forename: Hocine
authors.initials: H
authors.lastname: Madaoui
authors.forename: Raphaël
authors.initials: R
authors.lastname: Guérois
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Srivastava
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry; D014759:Viral Envelope Proteins / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; D003545:Cysteine