title: Determinants of human immunodeficiency virus type 1 envelope glycoprotein activation by soluble CD4 and monoclonal antibodies.
abstract: Infection by some human immunodeficiency virus type 1 (HIV-1) isolates is enhanced by the binding of subneutralizing concentrations of soluble receptor, soluble CD4 (sCD4), or monoclonal antibodies directed against the viral envelope glycoproteins. In this work, we studied the abilities of different antibodies to mediate activation of the envelope glycoproteins of a primary HIV-1 isolate, YU2, and identified the regions of gp120 envelope glycoprotein contributing to activation. Binding of antibodies to a variety of epitopes on gp120, including the CD4 binding site, the third variable (V3) loop, and CD4-induced epitopes, enhanced the entry of viruses containing YU2 envelope glycoproteins. Fab fragments of antibodies directed against either the CD4 binding site or V3 loop also activated YU2 virus infection. The activation phenotype was conferred on the envelope glycoproteins of a laboratory-adapted HIV-1 isolate (HXBc2) by replacing the gp120 V3 loop or V1/V2 and V3 loops with those of the YU2 virus. Infection by the YU2 virus in the presence of activating antibodies remained inhibitable by macrophage inhibitory protein 1beta, indicating dependence on the CCR5 coreceptor on the target cells. Thus, antibody enhancement of YU2 entry involves neither Fc receptor binding nor envelope glycoprotein cross-linking, is determined by the same variable loops that dictate enhancement by sCD4, and probably proceeds by a process fundamentally similar to the receptor-activated virus entry pathway.
authors.affiliation: Division of Human Retrovirology, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sullivan
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Binley
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: C F
authors.initials: CF
authors.lastname: Barbas
authors.forename: P W
authors.initials: PW
authors.lastname: Parren
authors.forename: D R
authors.initials: DR
authors.lastname: Burton
authors.forename: J
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D019556:COS Cells; D002478:Cells, Cultured; D054407:Chemokine CCL4; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000502:physiology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D054407:Chemokine CCL4; D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; C076613:recombinant soluble CD4