COVALENTLY CROSS-LINKED 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

Specific conformational changes in the envelope glycoprotein gp120 of the human immunodeficiency virus type-1 (HIV-1) may be critical for el iciting a broadly neutralizing immune response against primary virus i solates. Since the interaction of gp120 with its receptor, CD4, induce s conformational perturbations in both molecules, gp120-CD4 complexes should present unique immunogenic features that may include novel epit opes for broadly neutralizing antibodies. To test this hypothesis, we raised polyclonal antiserum against covalently crosslinked gp120-CD4 c omplexes in a goat and examined the ability of the anti-complex antibo dies to neutralize primary and laboratory-adapted HIV-1 isolates, In c ell-free neutralization assays with HIV-1(MN), the antiserum demonstra ted the ability to neutralize primary virus more effectively than the laboratory-adapted isolate. The neutralizing capacity of the anti-comp lex serum extended to primary isolates from distant genetic clades A, D, and E, although the degree of neutralization was found to vary amon g the clades. The neutralizing activity of the serum was composed of t wo components. The first component included anti-CD4 antibodies that r ecognized epitopes outside the gp120 binding site; the second was inde pendent of CD4 reactivity and was retained after removal of cell surfa ce anti-CD4 reactivity by repeated absorption with CD4-positive cells. These results demonstrate that gp120-CD4 complexes can elicit a uniqu e polyclonal antibody response that is relevant to the neutralization of primary isolates of HIV-1. (C) 1996 Academic Press, Inc.