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During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies. 10.1126/science.1192819

The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies. 5 May 2009; accepted 10 September 2009 10.1126/science.1175868

The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization., The HIV envelope spike mediates binding to receptors and virus entry [reviewed in (1)]. The trimeric spike is composed of three gp120 exterior and three gp41 transmembrane envelope glycoproteins. CD4 [...]

The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp1 20 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp1 20 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections., Most naturally occurring primate immunodeficiency viruses [HIV and simian immunodeficiency virus (SIV)] bind the Β-chemokine receptor CCR5 as an obligate step in virus entry into target cells (1, 2). The [...]

CCR5 and CD4 are coreceptors for immunodeficiency virus entry into target cells. The gp120 envelope glycoprotein from human immunodeficiency virus strain HIV-1(YU2) bound human CCR5 ([CCR5.sub.hu]) or rhesus macaque CCR5 ([CCR5.sub.rh]) only in the presence of CD4. The gp120 from simian immunodeficiency virus strain SIVmac239 bound [CCR5.sub.rh] without CD4, but [CCR5.sub.hu] remained CD4-dependent. The CD4-independent binding of SIVmac239 gp120 depended on a single amino acid, [Asp.sup.13], in the [CCR5.sub.rh] aminoterminus. Thus, CCR5-binding moieties on the immunodeficiency virus envelope glycoprotein can be generated by interaction with CD4 or by direct interaction with the CCR5 amino-terminus. These results may have implications for the evolution of receptor use among lentiviruses as well as utility in the development of effective intervention., HIV-1 entry is mediated by the viral envelope glycoprotein complex consisting of the exterior glycoprotein, gp120, and the transmembrane glycoprotein, gp41 (1). CD4 acts as the primary target cell receptor, [...]

Functional Regions of the Envelope Glycoprotein of Human Immunodeficiency Virus Type 1 THE HUMAN IMMUNODEFICIENCY virus type 1 (HIV-1), also called HTLV-III or LAV-1, is the etiological agent of the [...]

Replicative and Cytopathic Potential of HTLV-III/LAV with sor Gene Deletions THE HUMAN T-LYMPHOTROPIC VIrus type III (HTLV-III/LAV) is the primary etiological agent of the acquired immune deficiency syndrome (AIDS) and [...]

Trans-Activator Gene of HTLV-II Induces IL-2 Receptor and IL-2 Cellular Gene Expression THE HUMAN T-LYMPHOTROPIC VIruses types I and II (HTLV-I and -II) are associated with certain T-cell leukemias and [...]

Human T-cell lymphotropic virus type III (HTLV-III/LAV) is the etiological agent of the acquired immune deficiency syndrome (AIDS) and associated diseases (1). Like HTLV types I and II and the [...]

Human T-cell leukemia viruses (HTLV) comprise retroviral family associated with lymphoid disorders. HTLV types have been identified on the basis of immunocompetition analysis of gag proteins (1). HTLV-I is associates [...]

The genome of bovine leukemia virus (BLV) contains the long terminal repeat (LTR), gag, pol. and env sequences characteristic of all retroviruses (1). In addition, like the human T-cell leukemia [...]

The human T-cell leukemia viruses (HTLV) are retroviruses associated with disorders of the OKT4.sup.+ (helper) subset of T lymphocytes. HTLV type I (HTLV-I) is the probable etiologic agent of adult [...]

Subcellular Localization of the Product of the Long Open Reading Frame of Human T-Cell Leukemia Virus Type I Human T-cell leukemia virus type I (HTLV-I) is a retrovirus that is [...]

During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies. [ABSTRACT FROM AUTHOR]

The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies. [ABSTRACT FROM AUTHOR]

The (CR5 co-receptor binds to the HIV-1 gp120 envelope glycoprotein and facilitates HIV-1 entry into cells. Its N terminus is tyrosine-sulfated, as are many antibodies that react with the co-receptor binding site on gp120. We applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the (CR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 (a-helix) and 412d (extended- loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on (CR5 and on 412d induces similar structural rearrangements in gp120. These results now provide a framework for understanding HIV-1 interactions with the (CR5 N terminus during viral entry and define a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system. [ABSTRACT FROM AUTHOR]

The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization. [ABSTRACT FROM AUTHOR]