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Pathogenesis and Immunity

Stabilizing the HIV-1 Envelope Glycoprotein State 2A Conformation

Dani Vézina, Shang Yu Gong, William D. Tolbert, Shilei Ding, Dung Nguyen, Jonathan Richard, Gabrielle Gendron-Lepage, Bruno Melillo, Amos B. Smith III, Marzena Pazgier, Andrés Finzi
Guido Silvestri, Editor
Dani Vézina
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
bDépartement de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
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  • ORCID record for Dani Vézina
Shang Yu Gong
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
cDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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William D. Tolbert
dInfectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Shilei Ding
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
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Dung Nguyen
dInfectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Jonathan Richard
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
bDépartement de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
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Gabrielle Gendron-Lepage
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
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Bruno Melillo
eDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Amos B. Smith III
eDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Marzena Pazgier
dInfectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Andrés Finzi
aCentre de Recherche du CHUM, Montreal, Quebec, Canada
bDépartement de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
cDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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Guido Silvestri
Emory University
Roles: Editor
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DOI: 10.1128/JVI.01620-20
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ABSTRACT

The HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)3] is a metastable complex expressed at the surface of viral particles and infected cells that samples different conformations. Before engaging CD4, Env adopts an antibody-resistant “closed” conformation (State 1). CD4 binding triggers an intermediate conformation (State 2) and then a more “open” conformation (State 3) that can be recognized by nonneutralizing antibodies (nnAbs) such as those that recognize the coreceptor binding site (CoRBS). Binding of antibodies to the CoRBS permits another family of nnAbs, the anti-cluster A family of Abs which target the gp120 inner domain, to bind and stabilize an asymmetric conformation (State 2A). Cells expressing Env in this conformation are susceptible to antibody-dependent cellular cytotoxicity (ADCC). This conformation can be stabilized by small-molecule CD4 mimetics (CD4mc) or soluble CD4 (sCD4) in combination with anti-CoRBS Ab and anti-cluster A antibodies. The precise stoichiometry of each component that permits this sequential opening of Env remains unknown. Here, we used a cell-based enzyme-linked immunosorbent assay (CBE) to evaluate each component individually. In this assay, we used a “trimer mixing” approach by combining wild-type (wt) subunits with subunits impaired for CD4 or CoRBS Ab binding. This enabled us to show that State 2A requires all three gp120 subunits to be bound by sCD4/CD4mc and anti-CoRBS Abs. Two of these subunits can then bind anti-cluster A Abs. Altogether, our data suggest how this antibody-vulnerable Env conformation is stabilized.

IMPORTANCE Stabilization of HIV-1 Env State 2A has been shown to sensitize infected cells to ADCC. State 2A can be stabilized by a “cocktail” composed of CD4mc, anti-CoRBS, and anti-cluster A Abs. We present evidence that optimal State 2A stabilization requires all three gp120 subunits to be bound by both CD4mc and anti-CoRBS Abs. Our study provides valuable information on how to stabilize this ADCC-vulnerable conformation. Strategies aimed at stabilizing State 2A might have therapeutic utility.

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Stabilizing the HIV-1 Envelope Glycoprotein State 2A Conformation
Dani Vézina, Shang Yu Gong, William D. Tolbert, Shilei Ding, Dung Nguyen, Jonathan Richard, Gabrielle Gendron-Lepage, Bruno Melillo, Amos B. Smith III, Marzena Pazgier, Andrés Finzi
Journal of Virology Feb 2021, 95 (5) e01620-20; DOI: 10.1128/JVI.01620-20

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Stabilizing the HIV-1 Envelope Glycoprotein State 2A Conformation
Dani Vézina, Shang Yu Gong, William D. Tolbert, Shilei Ding, Dung Nguyen, Jonathan Richard, Gabrielle Gendron-Lepage, Bruno Melillo, Amos B. Smith III, Marzena Pazgier, Andrés Finzi
Journal of Virology Feb 2021, 95 (5) e01620-20; DOI: 10.1128/JVI.01620-20
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KEYWORDS

HIV-1
envelope glycoproteins
Env conformation
State 2A
nonneutralizing antibodies
CD4-induced antibodies
cluster A
coreceptor binding site
gp120
small CD4 mimetics
soluble CD4

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