title: Covalently crosslinked complexes of human immunodeficiency virus type 1 (HIV-1) gp120 and CD4 receptor elicit a neutralizing immune response that includes antibodies selective for primary virus isolates.
abstract: Specific conformational changes in the envelope glycoprotein gp120 of the human immunodeficiency virus type-1 (HIV-1) may be critical for eliciting a broadly neutralizing immune response against primary virus isolates. Since the interaction of gp120 with its receptor, CD4, induces conformational perturbations in both molecules, gp120-CD4 complexes should present unique immunogenic features that may include novel epitopes for broadly neutralizing antibodies. To test this hypothesis, we raised polyclonal antiserum against covalently crosslinked gp120-CD4 complexes in a goat and examined the ability of the anti-complex antibodies to neutralize primary and laboratory-adapted HIV-1 isolates. In cell-free neutralization assays with HIV-1MN, the antiserum demonstrated the ability to neutralize primary virus more effectively than the laboratory-adapted isolate. The neutralizing capacity of the anti-complex serum extended to primary isolates from distant genetic clades A, D, and E, although the degree of neutralization was found to vary among the clades. The neutralizing activity of the serum was composed of two components. The first component included anti-CD4 antibodies that recognized epitopes outside the gp120 binding site; the second was independent of CD4 reactivity and was retained after removal of cell surface anti-CD4 reactivity by repeated absorption with CD4-positive cells. These results demonstrate that gp120-CD4 complexes can elicit a unique polyclonal antibody response that is relevant to the neutralization of primary isolates of HIV-1.
authors.affiliation: Advanced BioScience Laboratories, Inc., 5510 Nicholson Lane, Kensington, Maryland, 20895, USA.
authors.forename: A
authors.initials: A
authors.lastname: Devico
authors.forename: A
authors.initials: A
authors.lastname: Silver
authors.forename: A M
authors.initials: AM
authors.lastname: Thronton
authors.forename: M G
authors.initials: MG
authors.lastname: Sarngadharan
authors.forename: R
authors.initials: R
authors.lastname: Pal
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000821:virology; D000818:Animals; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000276:immunology; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D002460:Cell Line; D003432:Cross-Linking Reagents; D015726:Giant Cells / Q000821:virology; D006041:Goats; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D009500:Neutralization Tests
chemical_list: D000936:Antigen-Antibody Complex; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120