title: Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.
abstract: To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.
authors.affiliation: Department of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. s.burastero@hsr.it
authors.forename: Samuele E
authors.initials: SE
authors.lastname: Burastero
authors.forename: Barbara
authors.initials: B
authors.lastname: Frigerio
authors.forename: Lucia
authors.initials: L
authors.lastname: Lopalco
authors.forename: Francesca
authors.initials: F
authors.lastname: Sironi
authors.forename: Daniela
authors.initials: D
authors.lastname: Breda
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Scarlatti
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.forename: Paolo
authors.initials: P
authors.lastname: Lusso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001483:Base Sequence; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D003168:Complement Fixation Tests; D000939:Epitopes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D006825:Hybridomas; D007106:Immune Sera / Q000276:immunology; D007114:Immunization; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D011323:Primates; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007106:Immune Sera