CD4-Induced conformational changes in the human immunodeficiency virus type 1 gp120 glycoprotein: consequences for virus entry and neutralization.
Human immunodeficiency virus type 1 (HIV-1) entry into target cells involves sequential binding of the gp120 exterior envelope glycoprotein to CD4 and to specific chemokine receptors. Soluble CD4 (sCD4) is thought to mimic membrane-anchored CD4, and its binding alters the conformation of the HIV-1 envelope glycoproteins. Two cross-competing monoclonal antibodies, 17b and CG10, that recognize CD4-inducible gp120 epitopes and that block gp120-chemokine receptor binding were used to investigate the nature and functional significance of gp120 conformational changes initiated by CD4 binding. Envelope glycoproteins derived from both T-cell line-adapted and primary HIV-1 isolates exhibited increased binding of the 17b antibody in the presence of sCD4. CD4-induced exposure of the 17b epitope on the oligomeric envelope glycoprotein complex occurred over a wide range of temperatures and involved movement of the gp120 V1/V2 variable loops. Amino acid changes that reduced the efficiency of 17b epitope exposure following CD4 binding invariably compromised the ability of the HIV-1 envelope glycoproteins to form syncytia or to support virus entry. Comparison of the CD4 dependence and neutralization efficiencies of the 17b and CG10 antibodies suggested that the epitopes for these antibodies are minimally accessible following attachment of gp120 to cell surface CD4. These results underscore the functional importance of these CD4-induced changes in gp120 conformation and illustrate viral strategies for sequestering chemokine receptor-binding regions from the humoral immune response.
Sullivan
N
N
Division of Human Retrovirology, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sun
Y
Y
Sattentau
Q
Q
Thali
M
M
Wu
D
D
Denisova
G
G
Gershoni
J
J
Robinson
J
J
Moore
J
J
Sodroski
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D015704:CD4 Antigens / Q000737:chemistry* / Q000502:physiology; D019556:COS Cells; D003432:Cross-Linking Reagents; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D011487:Protein Conformation; D013696:Temperature; D014779:Virus Replication
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D015699:HIV Envelope Protein gp120