Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1

Yang, Xinzhen; Kurteva, Svetla; Lee, Sandra; Sodroski, Joseph

doi:10.1128/jvi.79.6.3500-3508.2005

Cited by 89 publications

(148 citation statements)

References 84 publications

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“…We inferred that one 2F5 antibody molecule was sufficient when its epitope was in functional SU or TM because X2Y1 and X1Y2 species were neutralized with equal efficiency and neutralization occurred even at DNA ratios at which most heterotrimers would carry a single 2F5 epitope. The same conclusion has been reached by others (37,43). We previously showed that the 2F5 antibody slightly inhibited but did not prevent virions with 2F5 epitopes in SU from binding to cells with the mCAT1 receptor (25).…”

Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

“…Different antibodies may have different mechanisms. Stoichiometry of antibody binding for neutralization has been extensively studied, but debate about how many antibody molecules need to bind per virion for neutralization continues (4,16,17,37,43).In this study, we address questions concerning the stoichiometry of MLV Env-mediated fusion and its inhibition by antibody, including how many functional SU or TM molecules are required for an Env trimer to be fusion competent; how many antibody molecules are needed to block the function of one trimer; whether the stoichiometry of neutralization is the same for an epitope in SU as in TM; and whether antibodies can inactivate a trimer by binding only to nonfunctional SU or TM in the trimer and, if so, whether they are as efficient in this case as when they bind to functional molecules.Our strategy is based on MLV Env complementation (47, 48) and our previous work showing that 2F5 blocks membrane …”

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confidence: 99%

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Stoichiometry of Murine Leukemia Virus Envelope Protein-Mediated Fusion and Its Neutralization

Silver

2006

J Virol

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Envelope glycoproteins (Envs) of retroviruses form trimers that mediate fusion between viral and cellular membranes and are the targets for neutralizing antibodies. Understanding in detail how Env trimers mediate membrane fusion, and how antibodies interfere with this process, is a fundamental problem in biology with practical implications for the development of antiviral drugs and vaccines. We investigated the stoichiometry of Env-mediated fusion and its inhibition by antibody by inserting an epitope from human immunodeficiency virus for a neutralizing antibody (2F5) into the surface (SU) or transmembrane (TM) protein of murine leukemia virus Env, along with point mutations that abrogate SU and TM function but complement one another. We transfected various combinations of these Env genes and investigated Env-mediated cell fusion and its inhibition by 2F5 antibody. Our results showed that heterotrimers with one functional SU molecule were fusion competent in complementation experiments and that one antibody molecule was sufficient to inactivate the fusion function of a trimer when its epitope was in functional SU or TM. 2F5 antibody could also neutralize trimers with the 2F5 epitope in nonfunctional SU or TM, but less efficiently.Infection by enveloped viruses starts with fusion between viral and cellular membranes, which is mediated by envelope glycoproteins (Envs), usually organized as oligomers. For murine leukemia virus (MLV) and human immunodeficiency virus type 1 (HIV-1), the Env proteins trimerize and become glycosylated in the endoplasmic reticulum en route to the Golgi body. In the Golgi body, sugars are modified and Env is proteolytically cleaved into a surface protein species designated SU and a transmembrane protein designated TM, which are linked through a disulfide bond in MLV (7,8,14). Following transfer to the cell surface and incorporation into virus particles, the cytoplasmic tail of the MLV Env is cleaved by the viral protease, a step that is necessary to activate the fusogenic potential of MLV Env (12,30,31). Binding of SU to its cellular receptor(s) induces conformational changes in SU that expose the fusion machinery of TM; TM then pulls viral and cellular membranes together by forming a trimer of hairpin-like structures common to many different viral Envs (6,8,10,11,[39][40][41].While MLV and HIV-1 Envs function as trimers, not all of the molecules in a trimer need to be functional. Thus, some Env mutants form functional heterotrimers with wild-type Env (44), and some Envs with lethal mutations in SU can complement Envs with lethal mutations in TM (35,47). Two kinds of heterotrimers may be formed, which can be designated X2Y1 and X1Y2, where X and Y stand for the different monomers and 1 and 2 stand for the number of monomers of each type in a trimer. A recent study found that trimers with one but not two mutant monomers were functional (44). Whether one or both forms of heterotrimer are functional is relevant to a detailed understanding of the mechanism by which Env induces membrane fusio...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Stoichiometry of Murine Leukemia Virus Envelope Protein-Mediated Fusion and Its Neutralization

Silver

2006

J Virol

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“…Their model applies to antibodies differing in neutralizing potency and to virus isolates with different neutralization sensitivities. 13 There is yet another group of functional antibodies that do not neutralize the virus but may exert protective efficacy by inducing antibody dependent cell cytotoxicity (ADCC) i.e., they direct the killing of infected cells through recognition of viral proteins on cell surfaces.…”

Section: Mechanisms Of Antibody Mediated Protectionmentioning

confidence: 99%

Role of Neutralizing Antibodies in Protective Immunity Against HIV

Srivastava

Ulmer²,

Barnett³

2005

Human Vaccines

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“…It is difficult to reconcile binding of a large Ab (150 kDa) to a small surface glycoprotein (46 kDa) without loss of protein function. Indeed, for HIV-1, a compelling argument has been made that if an Ab binds to the wildtype envelope complex, it will neutralize (54)(55)(56)(57). Consistent with this notion, a heterologous Ab can inhibit and neutralize HIV-1 infectivity when the epitope recognized by that Ab is engineered into the gp120 subunit of HIV-1 envelope (56, 57).…”

Section: Discussionmentioning

confidence: 78%

Antibodies to the Envelope Glycoprotein of Human T Cell Leukemia Virus Type 1 Robustly Activate Cell-Mediated Cytotoxic Responses and Directly Neutralize Viral Infectivity at Multiple Steps of the Entry Process

Kuo

Mirsaliotis

Brighty

2011

The Journal of Immunology

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Infection of human cells by human T cell leukemia virus type 1 (HTLV-1) is mediated by the viral envelope glycoproteins. The gp46 surface glycoprotein binds to cell surface receptors, including heparan sulfate proteoglycans, neuropilin 1, and glucose transporter 1, allowing the transmembrane glycoprotein to initiate fusion of the viral and cellular membranes. The envelope glycoproteins are recognized by neutralizing Abs and CTL following a protective immune response, and therefore, represent attractive components for a HTLV-1 vaccine. To begin to explore the immunological properties of potential envelope-based subunit vaccine candidates, we have used a soluble recombinant surface glycoprotein (gp46, SU) fused to the Fc region of human IgG (sRgp46-Fc) as an immunogen to vaccinate mice. The recombinant SU protein is highly immunogenic and induces high titer Ab responses, facilitating selection of hybridomas that secrete mAbs targeting SU. Many of these mAbs recognize envelope displayed on the surface of HTLV-1–infected cells and virions and several of the mAbs robustly antagonize envelope-mediated membrane fusion and neutralize pseudovirus infectivity. The most potently neutralizing mAbs recognize the N-terminal receptor-binding domain of SU, though there is considerable variation in neutralizing proficiency of the receptor-binding domain-targeted mAbs. By contrast, Abs targeting the C-terminal domain of SU tend to lack robust neutralizing activity. Importantly, we find that both neutralizing and poorly neutralizing Abs strongly stimulate neutrophil-mediated cytotoxic responses to HTLV-1–infected cells. Our data demonstrate that recombinant forms of SU possess immunological features that are of significant utility to subunit vaccine design.

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Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1

Cited by 89 publications

References 84 publications

Stoichiometry of Murine Leukemia Virus Envelope Protein-Mediated Fusion and Its Neutralization

Stoichiometry of Murine Leukemia Virus Envelope Protein-Mediated Fusion and Its Neutralization

Role of Neutralizing Antibodies in Protective Immunity Against HIV

Antibodies to the Envelope Glycoprotein of Human T Cell Leukemia Virus Type 1 Robustly Activate Cell-Mediated Cytotoxic Responses and Directly Neutralize Viral Infectivity at Multiple Steps of the Entry Process

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