Dataset Information

Enhancing Virion Tethering by BST2 Sensitizes Productively and Latently HIV-infected T cells to ADCC Mediated by Broadly Neutralizing Antibodies.

ABSTRACT: Binding of anti-HIV antibodies (Abs) to envelope (Env) glycoproteins on infected cells can mark them for elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). BST2, a type I interferon (IFN)-stimulated restriction factor that anchors nascent Env-containing virions at the surface of infected cells has been shown to enhance ADCC functions. In a comprehensive analysis of ADCC potency by neutralizing anti-HIV Abs (NAbs), we show in this study that NAbs are capable of mediating ADCC against HIV-infected T cells with 3BNC117, PGT126 and PG9 being most efficient. We demonstrate that HIV-induced BST2 antagonism effectively attenuates Ab binding and ADCC responses mediated by all classes of NAbs that were tested. Interestingly, IFN? treatment can reverse this effect in a BST2-dependent manner. Importantly, while reactivated latent T cell lines display some susceptibility to ADCC mediated by broadly NAbs, inactivating BST2 viral countermeasures and/or exogenous IFN? augment their elimination. Overall, our findings support the notion that NAbs can induce ADCC. They highlight that while BST2 antagonism by HIV promotes ADCC evasion, strategies aimed at restoring BST2 restriction could improve anti-HIV responses and potentially provide a means to eliminate reactivated cells in latent reservoirs.

SUBMITTER: Pham TN

PROVIDER: S-EPMC5112552 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Enhancing Virion Tethering by BST2 Sensitizes Productively and Latently HIV-infected T cells to ADCC Mediated by Broadly Neutralizing Antibodies.

Pham Tram N Q TN Lukhele Sabelo S Dallaire Frédéric F Perron Gabrielle G Cohen Éric A ÉA

Scientific reports 20161117

Binding of anti-HIV antibodies (Abs) to envelope (Env) glycoproteins on infected cells can mark them for elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). BST2, a type I interferon (IFN)-stimulated restriction factor that anchors nascent Env-containing virions at the surface of infected cells has been shown to enhance ADCC functions. In a comprehensive analysis of ADCC potency by neutralizing anti-HIV Abs (NAbs), we show in this study that NAbs are capable of mediating ADCC a ...[more]

PMID: 27853288

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Project description:Rotavirus live-attenuated vaccines, both mono- and pentavalent, generate broadly heterotypic protection. B-cells isolated from adults encode neutralizing antibodies, some with affinity for VP5*, that afford broad protection in mice. We have mapped the epitope of one such antibody by determining the high-resolution cryo-EM structure of its antigen-binding fragment (Fab) bound to the virion of a candidate vaccine strain, CDC-9. The Fab contacts both the distal end of a VP5* β-barrel domain and the two VP8* lectin-like domains at the tip of a projecting spike. Its interactions with VP8* do not impinge on the likely receptor-binding site, suggesting that the mechanism of neutralization is at a step subsequent to initial attachment. We also examined structures of CDC-9 virions from two different stages of serial passaging. Nearly all the VP4 (cleaved to VP8*/VP5*) spikes on particles from the earlier passage (wild-type isolate) had transitioned from the "upright" conformation present on fully infectious virions to the "reversed" conformation that is probably the end state of membrane insertion, unable to mediate penetration, consistent with the very low in vitro infectivity of the wild-type isolate. About half the VP4 spikes were upright on particles from the later passage, which had recovered substantial in vitro infectivity but had acquired an attenuated phenotype in neonatal rats. A mutation in VP4 that occurred during passaging appears to stabilize the interface at the apex of the spike and could account for the greater stability of the upright spikes on the late-passage, attenuated isolate. IMPORTANCE Rotavirus live-attenuated vaccines generate broadly heterotypic protection, and B-cells isolated from adults encode antibodies that are broadly protective in mice. Determining the structural and mechanistic basis of broad protection can contribute to understanding the current limitations of vaccine efficacy in developing countries. The structure of an attenuated human rotavirus isolate (CDC-9) bound with the Fab fragment of a broadly heterotypic protective antibody shows that protection is probably due to inhibition of the conformational transition in the viral spike protein (VP4) critical for viral penetration, rather than to inhibition of receptor binding. A comparison of structures of CDC-9 virus particles at two stages of serial passaging supports a proposed mechanism for initial steps in rotavirus membrane penetration.

Dataset Information

Enhancing Virion Tethering by BST2 Sensitizes Productively and Latently HIV-infected T cells to ADCC Mediated by Broadly Neutralizing Antibodies.

Publications

Enhancing Virion Tethering by BST2 Sensitizes Productively and Latently HIV-infected T cells to ADCC Mediated by Broadly Neutralizing Antibodies.

Similar Datasets

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