title: Progress towards the development of a HIV-1 gp41-directed vaccine.
abstract: The HIV-1 gp41 envelope glycoprotein mediates fusion of the viral and cellular membranes. The core of the gp41 ectodomain undergoes a receptor-triggered conformational transition forming a trimeric, alpha-helical coiled-coil structure. This trimer-of-hairpins species facilitates insertion of the viral envelope protein into the host cell membrane promoting viral entry. The prefusogenic conformation of gp41 is capable of stimulating a neutralizing antibody immune response and is therefore an attractive therapeutic target. Several broadly neutralizing HIV-1 monoclonal antibodies which bind to gp41 have been characterized and include 4E10, Z13 and 2F5. A conserved segment of gp41 (residues 661-684) has been identified as the epitope for the HIV-1 neutralizing antibody 2F5 (MAb 2F5). MAb 2F5 has attracted considerable attention because of the highly conserved recognition epitope and the ability to neutralize both laboratory-adapted and primary viral isolates. Antibodies which recognize the immunodominant regions of gp41 may provide protection against HIV infection if elicited at appropriate concentrations. Here we review the rational design, structure-activity relationships and conformational features of both linear and constrained peptide immunogens incorporating variants of both the 2F5 epitope and the gp41 ectodomain. This review describes a rational design approach combining structural characterization with traditional SAR to optimize MAb 2F5 antibody affinities of gp41-based peptide immunogens. The immunogens are shown to stimulate a high titer, peptide-specific immune response; however, the resulting antisera were incapable of viral neutralization. The implication of these findings with regard to structural and immunological considerations is discussed.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA. georgia_mcgaughey@merck.com
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Gaetano
authors.initials: G
authors.lastname: Barbato
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Roger M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: Victor M
authors.initials: VM
authors.lastname: Garsky
authors.forename: William M
authors.initials: WM
authors.lastname: Hurni
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Joyce
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bogusky
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D017124:Conserved Sequence; D015195:Drug Design; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D022223:Vaccines, Subunit