Stabilizing the HIV-1 envelope glycoprotein State 2A conformation
The HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41) ] 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 trigg...
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Published in | Journal of virology Vol. 95; no. 5 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
01.03.2021
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Subjects | |
Online Access | Get full text |
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Summary: | The HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)
] 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 non-neutralizing 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 ELISA (CBE) assay 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 suggests how this antibody vulnerable Env conformation is stabilized.
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Vézina D, Gong SY, Tolbert WD, Ding S, Nguyen D, Richard J, Gendron-Lepage G, Melillo B, Smith AB, III, Pazgier M, Finzi A. 2021. Stabilizing the HIV-1 envelope glycoprotein State 2A conformation. J Virol 95:e01620-20. https://doi.org/10.1128/JVI.01620-20. |
ISSN: | 0022-538X 1098-5514 |
DOI: | 10.1128/JVI.01620-20 |