title: Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold.
abstract: V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.
authors.affiliation: Molsoft LLC, 3366 N Torrey Pines Ct., La Jolla, CA 92037, USA. max@molsoft.com
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
authors.forename: Xunqing
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
authors.forename: Sandra
authors.initials: S
authors.lastname: Cohen
authors.forename: Chavdar
authors.initials: C
authors.lastname: Krachmarov
authors.forename: Aidy
authors.initials: A
authors.lastname: Salomon
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.forename: Abraham
authors.initials: A
authors.lastname: Pinter
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
mesh_terms: D016915:AIDS Vaccines; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D002772:Cholera Toxin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015195:Drug Design; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D007114:Immunization; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011817:Rabbits
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D002772:Cholera Toxin