Single amino-acid changes in HIV envelope affect viral tropism and receptor binding

Abstract

Infection by the human immunodeficiency virus (HIV) is initiated by the binding of its extracellular envelope glycoprotein, gp120, to the CD4 antigen on target cells. To map the residues of the HIV-1 glycoprotein that are critical for binding and to analyse the effects of binding on viral infectivity, we created 15 mutations in a region of gp120 that is important for binding to CD4 (refs 4,5). We find that substitution of a single amino acid (tryptophan at position 432) can abrogate CD4 binding and that virus carrying this mutation is non-infectious. By contrast, other amino-acid changes in the same region do not affect CD4 binding but restrict viral tropism: virions containing isoleucine substitutions at position 425 lose their ability to infect a monocyte cell line (U937 cells) but can still infect T-lymphocyte cell lines (CEM, SUP-T1) and activated human peripheral blood lymphocytes. These results indicate that cellular tropism of HIV can be influenced by a single amino-acid change in gp120.

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

“…Residues in contact are concentrated in the span from 25 to 64 of CD4, but they are distributed over six segments of gp120 (Figs 2d and 3i): one residue from the V1/V2 stem, loop ℒD, the β15-α3 excursion, the β20-β21 hairpin, strand β23 and the β24-α5 connection. These interactions are compatible with previous analyses of mutational data on both CD4 (refs 11,12,29 ) and gp120 (refs 3,13,14 ). Other groups are also involved, including some at gp120 sites that have not been tested, but residues identified as critical for binding do indeed interact with one another (Fig.…”

“…10 ) have been determined, and mutagenesis indicates that the CD4 structure analogous to the second complementarity-determining region (CDR2) of immunoglobulins is critical for gp120 binding 11,12 . Conserved gp120 residues important for CD4 binding have likewise been identified by mutagenesis 3,13,14 .…”

“…10 ) have been determined, and mutagenesis indicates that the CD4 structure analogous to the second complementarity-determining region (CDR2) of immunoglobulins is critical for gp120 binding 11,12 . Conserved gp120 residues important for CD4 binding have likewise been identified by mutagenesis 3,13,14 .CD4 binding induces conformational changes in the gp120 glycoprotein, some of which involve the exposure and/or formation of a binding site for specific chemokine receptors. These chemokine receptors, mainly CCR5 and CXCR4 for HIV-1, serve as obligate second receptors for virus entry 15,16 .…”

Binding of equine infectious anemia virus to the equine lentivirus receptor-1 is mediated by complex discontinuous sequences in the viral envelope gp90 protein

“…In contrast, the simple retroviruses, such as avian and murine oncoviruses, employ a single cell receptor to infect target cells. This difference in receptor specificity between oncoviruses and lentiviruses also appears to be related to differences in the nature of the respective receptor-binding domains of HIV-1 gp120 and murine gp70 (Cordonnier et al, 1989;Fass et al, 1997;Battini et al, 1998;. For example, the CD4-binding site of gp120 is a depression formed at the interface of the outer domain with the inner domain and the bridging sheet of gp120 spanning a complex of discontinuous sequences, mainly in the C-terminal half of gp120.…”

“…The first four variable regions form surface-exposed loops that contain disulfide bonds at their bases (Leonard et al, 1990;Moore et al, 1994). The conserved gp120 regions fold into a core that contains many discontinuous structures important for interactions in receptor binding (Cordonnier et al, 1989;Wyatt et al, 1998). HIV-1 gp120 binding to co-receptors requires that gp120 first binds CD4 (Wyatt et al, 1995;Rizzuto et al, 1998;.…”