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Abstract

We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.

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HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors.

Stephen Migueles, Alisha C Laborico, W Shupert … (2002)

It is unclear why immunological control of HIV replication is incomplete in most infected individuals. We examined here the CD8+ T cell response to HIV-infected CD4+ T cells in rare patients with immunological control of HIV. Although high frequencies of HIV-specific CD8+ T cells were present in nonprogressors and progressors, only those of nonprogressors maintained a high proliferative capacity. This proliferation was coupled to increases in perforin expression. These results indicated that nonprogressors were differentiated by increased proliferative capacity of HIV-specific CD8+ T cells linked to enhanced effector function. In addition, the relative absence of these functions in progressors may represent a mechanism by which HIV avoids immunological control.

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Structural definition of a conserved neutralization epitope on HIV-1 gp120

Tongqing Zhou, Ling Xu, Barna Dey … (2007)

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1. Supplementary information The online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.

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The antigenic structure of the HIV gp120 envelope glycoprotein.

R. Wyatt, P Kwong, E. Anne Desjardins … (1998)

The human immunodeficiency virus HIV-1 establishes persistent infections in humans which lead to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into a trimeric complex that mediates virus entry into target cells. HIV-1 entry depends on the sequential interaction of the gp120 exterior envelope glycoprotein with the receptors on the cell, CD4 and members of the chemokine receptor family. The gp120 glycoprotein, which can be shed from the envelope complex, elicits both virus-neutralizing and non-neutralizing antibodies during natural infection. Antibodies that lack neutralizing activity are often directed against the gp120 regions that are occluded on the assembled trimer and which are exposed only upon shedding. Neutralizing antibodies, by contrast, must access the functional envelope glycoprotein complex and typically recognize conserved or variable epitopes near the receptor-binding regions. Here we describe the spatial organization of conserved neutralization epitopes on gp120, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. A large fraction of the predicted accessible surface of gp120 in the trimer is composed of variable, heavily glycosylated core and loop structures that surround the receptor-binding regions. Understanding the structural basis for the ability of HIV-1 to evade the humoral immune response should assist in the design of a vaccine.

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PubMed ID:: 17721546

PMC ID:: 2584972

DOI:: 10.1038/nm1624

ScienceOpen disciplines: Chemistry

Keywords: Acquired Immunodeficiency Syndrome,blood,immunology,Antigens, CD,Antigens, CD4,Binding Sites, Antibody,Cohort Studies,HIV Antibodies,HIV-1,Humans,Neutralization Tests

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ScienceOpen disciplines: Chemistry

Keywords: Acquired Immunodeficiency Syndrome, blood, immunology, Antigens, CD, Antigens, CD4, Binding Sites, Antibody, Cohort Studies, HIV Antibodies, HIV-1, Humans, Neutralization Tests

Broad HIV-1 neutralization mediated by CD4-binding site antibodies.

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Most cited references 10

HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors.

Structural definition of a conserved neutralization epitope on HIV-1 gp120

The antigenic structure of the HIV gp120 envelope glycoprotein.

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