scholarly journals Elicitation of Cluster A and Co-Receptor Binding Site Antibodies Are Required to Eliminate HIV-1 Infected Cells

2020 ◽  
Vol 8 (5) ◽  
pp. 710 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Jérémie Prévost ◽  
Gabrielle Gendron-Lepage ◽  
Bruno Melillo ◽  
Junhua Chen ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Glycoprotein ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Receptor Binding Site ◽  
Coreceptor Binding ◽  
Infected Cells ◽  
Cluster A ◽  
Hiv 1 ◽  
Coreceptor Binding Site

HIV-1-infected individuals raise a polyclonal antibody response targeting multiple envelope glycoprotein (Env) epitopes. Interestingly, two classes of non-neutralizing CD4-induced (CD4i) antibodies, present in the majority of HIV-1-infected individuals have been described to mediate antibody-dependent cellular cytotoxicity (ADCC) in the presence of small CD4 mimetic compounds (CD4mc). These antibodies recognize the coreceptor binding site (CoRBS) and the constant region one and two (C1C2 or inner domain cluster A) of the gp120. In combination with CD4mc they have been shown to stabilize an antibody-vulnerable Env conformation, known as State 2A. Here we evaluated the importance of these two families of Abs in ADCC responses by immunizing guinea pigs with gp120 immunogens that have been modified to elicit or not these types of antibodies. Underlying the importance of anti-CoRBS and anti-cluster A Abs in stabilizing State 2A, ADCC responses were only observed in the presence of these two types of CD4i antibodies. Altogether, our results suggest that these two families of CD4i antibodies must be taken into account when considering future strategies relying on the use of CD4mc to eliminate HIV-1-infected cells in vivo.

scholarly journals Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Sai Priya Anand ◽  
Jérémie Prévost ◽  
Sophie Baril ◽  
Jonathan Richard ◽  
Halima Medjahed ◽  
...  
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Envelope Glycoproteins ◽  
Cellular Cytotoxicity ◽  
Fc Gamma Receptors ◽  
Coreceptor Binding ◽  
Infected Cells ◽  
Cluster A ◽  
Hiv 1 ◽  
Coreceptor Binding Site

ABSTRACTHIV-1 conceals epitopes of its envelope glycoproteins (Env) recognized by antibody (Ab)-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These Abs, including anti-coreceptor binding site (CoRBS) and anti-cluster A antibodies, preferentially recognize Env in its “open” conformation. The binding of anti-CoRBS Abs has been shown to induce conformational changes that further open Env, allowing interaction of anti-cluster A antibodies. We explored the possibility that CoRBS Abs synergize with anti-cluster A Abs to engage Fc-gamma receptors to mediate ADCC. We found that binding of anti-CoRBS and anti-cluster A Abs to the same gp120 is required for interaction with soluble dimeric FcγRIIIa in enzyme-linked immunosorbent assays (ELISAs). We also found that Fc regions of both Abs are required to optimally engage FcγRIIIa and mediate robust ADCC. Taken together, our results indicate that these two families of Abs act together in a sequential and synergistic fashion to promote FcγRIIIa engagement and ADCC.IMPORTANCEThe “open” CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV-positive (HIV+) sera, such as anti-coreceptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcγRIIIa and mediate ADCC.

scholarly journals Across Functional Boundaries: Making Nonneutralizing Antibodies To Neutralize HIV-1 and Mediate Fc-Mediated Effector Killing of Infected Cells

mBio ◽  
2021 ◽  
Author(s):  
Jonathan Richard ◽  
Dung N. Nguyen ◽  
William D. Tolbert ◽  
Romain Gasser ◽  
Shilei Ding ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Site ◽  
Host Cell ◽  
Constant Region ◽  
Antibody Recognition ◽  
Coreceptor Binding ◽  
Infected Cells ◽  
Cluster A ◽  
Hiv 1 ◽  
Coreceptor Binding Site

Highly conserved epitopes within the coreceptor binding site (CoRBS) and constant region 1 and 2 (C1-C2 or cluster A) are only available for antibody recognition after the HIV-1 Env trimer binds host cell CD4; therefore, they are not accessible on virions and infected cells, where the expression of CD4 is downregulated. Here, we have developed new antibody fusion molecules in which domains 1 and 2 of soluble human CD4 are linked with monoclonal antibodies of either the CoRBS or cluster A specificity.

scholarly journals Soluble Envelope Glycoprotein Trimers from a CD4-Independent HIV-1 Elicit Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies in Guinea Pigs

2015 ◽  
Vol 89 (20) ◽  
pp. 10707-10711 ◽  
Author(s):  
Marta K. Murray ◽  
Victor A. Teran ◽  
Jean-Philippe Chapleau ◽  
Baomin Wang ◽  
Su Hyon Kim ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Glycoprotein ◽  
Guinea Pigs ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Coreceptor Binding ◽  
Hiv 1 ◽  
Coreceptor Binding Site

CD4-independent HIV-1 variants can infect coreceptor-expressing cells lacking CD4. The envelope (Env) glycoproteins on these HIV-1 variants expose a coreceptor binding site that overlaps some CD4-induced (CD4i) epitopes. Reports have demonstrated that CD4i antibodies mediate antibody-dependent cellular cytotoxicity (ADCC). Here we investigated the immunogenicity of soluble Env trimers (sgp140) from a CD4-independent HIV-1 in guinea pigs and found that the sgp140 elicited ADCC-mediating antibodies. Therefore, these sgp140 might be useful in vaccine regimens aimed at eliciting ADCC responses.

scholarly journals Heparan Sulfate Targets the HIV-1 Envelope Glycoprotein gp120 Coreceptor Binding Site

2005 ◽  
Vol 280 (22) ◽  
pp. 21353-21357 ◽  
Author(s):  
Romain R. Vivès ◽  
Anne Imberty ◽  
Quentin J. Sattentau ◽  
Hugues Lortat-Jacob
Keyword(s):  
Heparan Sulfate ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Envelope Glycoprotein Gp120 ◽  
Coreceptor Binding ◽  
Glycoprotein Gp120 ◽  
Hiv 1 ◽  
Coreceptor Binding Site

scholarly journals Stabilizing the HIV-1 envelope glycoprotein State 2A conformation

2020 ◽  
Author(s):  
Dani Vézina ◽  
Shang Yu Gong ◽  
William D. Tolbert ◽  
Shilei Ding ◽  
Dung Nguyen ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Coreceptor Binding ◽  
Viral Particles ◽  
A Cell ◽  
Infected Cells ◽  
Cluster A ◽  
State 1 ◽  
Hiv 1 ◽  
Conformation State

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 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. 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.

scholarly journals Use of a gp120 Binding Assay To Dissect the Requirements and Kinetics of Human Immunodeficiency Virus Fusion Events

1999 ◽  
Vol 73 (12) ◽  
pp. 10346-10358 ◽  
Author(s):  
Benjamin J. Doranz ◽  
Sarah S. W. Baik ◽  
Robert W. Doms
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Chemokine Receptor ◽  
Elevated Temperatures ◽  
Receptor Binding Site ◽  
Gp120 Binding ◽  
Coreceptor Binding ◽  
Kinetics Of ◽  
Hiv 1 ◽  
Coreceptor Binding Site

ABSTRACT Binding of the extracellular subunit of human immunodeficiency type 1 (HIV-1) envelope (Env) glycoprotein (gp120) to CD4 triggers the induction or exposure of a highly conserved coreceptor binding site in gp120 that helps mediate membrane fusion. Characterizing the structural features involved in gp120-coreceptor binding and the conditions under which binding occurs is important for understanding the fusion process, the evolution of pathogenic strains in vivo, the identification of novel anti-HIV compounds, and the development of HIV vaccines that utilize triggered structures of Env. Here we use the kinetics of interaction between CCR5 and gp120 to understand temporal and structural changes that occur during viral fusion. Using saturation binding and homologous competition analysis, we estimated theKd of interaction between CCR5 and gp120 from the macrophage tropic HIV-1 strain JRFL to be 4 nM. Unlike Env-mediated fusion, gp120 binding to CCR5 did not require divalent cations or elevated temperatures. Binding was not significantly affected by the pH of binding, G-protein coupling of CCR5, or partial gp120 deglycosylation. Oligomeric, uncleaved JRFL gp140 failed to bind CCR5 despite its ability to bind CD4 and monoclonal antibody 17b, suggesting that the uncleaved ectodomain of gp41 interferes with full exposure of the chemokine receptor binding site. Exposure of the chemokine receptor binding site on gp120 could be induced rapidly by CD4, but exposure of this site was lost upon CD4 dissociation from gp120, indicating that the conformational changes in gp120 induced by CD4 binding are fully reversible. The functional gp120-soluble CD4 complex was remarkably stable over time and temperature ranges, offering the possibility that complexes in which the highly conserved coreceptor binding site in gp120 is exposed can be used for vaccine development.

scholarly journals Antigenic conservation and immunogenicity of the HIV coreceptor binding site

2005 ◽  
Vol 201 (9) ◽  
pp. 1407-1419 ◽  
Author(s):  
Julie M. Decker ◽  
Frederic Bibollet-Ruche ◽  
Xiping Wei ◽  
Shuyi Wang ◽  
David N. Levy ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Site ◽  
Natural Infection ◽  
Human Infection ◽  
Immune Recognition ◽  
Humoral Immune ◽  
Coreceptor Binding ◽  
Hiv 1 ◽  
Coreceptor Binding Site

Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1–infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1–infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.

scholarly journals Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Sai Priya Anand ◽  
Jonathan R. Grover ◽  
William D. Tolbert ◽  
Jérémie Prévost ◽  
Jonathan Richard ◽  
...  
Keyword(s):  
Immune Responses ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Surface Expression ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibodies ◽  
Closed Conformation ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT To minimize immune responses against infected cells, HIV-1 limits the surface expression of its envelope glycoprotein (Env). Here, we demonstrate that this mechanism is specific for the Env conformation and affects the efficiency of antibody-dependent cellular cytotoxicity (ADCC). Using flow cytometry and confocal microscopy, we show that broadly neutralizing antibodies (bNAbs) targeting the “closed” conformation of Env induce its internalization from the surface. In contrast, non-neutralizing antibodies (nNAbs) are displayed on the cell surface for prolonged period of times. The bNAb-induced Env internalization can be decreased by blocking dynamin function, which translates into higher susceptibilities of infected cells to ADCC. Our results suggest that antibody-mediated Env internalization is a mechanism used by HIV-1 to evade immune responses against the “closed” conformation of Env expressed on HIV-1-infected cells. IMPORTANCE HIV-1 has evolved to acquire several strategies to limit the exposure of its envelope glycoproteins (Env) on the surface of infected cells. In this study, we show that antibody-induced Env internalization is conformation specific and reduces the susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). Thus, a better understanding of this mechanism might help develop antibodies with improved capacities to mediate ADCC.

scholarly journals Multiple Interactions across the Surface of the gp120 Core Structure Determine the Global Neutralization Resistance Phenotype of Human Immunodeficiency Virus Type 1

2003 ◽  
Vol 77 (14) ◽  
pp. 8061-8071 ◽  
Author(s):  
Peter Bouma ◽  
Maria Leavitt ◽  
Peng Fei Zhang ◽  
Igor A. Sidorov ◽  
Dimiter S. Dimitrov ◽  
...  
Keyword(s):  
Binding Site ◽  
V3 Loop ◽  
Functional Interactions ◽  
Coreceptor Binding ◽  
Immunodeficiency Virus ◽  
Gp120 Core ◽  
Hiv 1 ◽  
Coreceptor Binding Site ◽  
Primary Virus

ABSTRACT Resistance to neutralization is an important characteristic of primary isolates of human immunodeficiency virus type 1 (HIV-1) that relates to the potential for successful vaccination to prevent infection and use of immunotherapeutics for treatment of established infection. In order to further elucidate mechanisms responsible for neutralization resistance, we studied the molecular mechanisms that determine the resistance of the primary virus isolate of the strain HIV-1 MN to neutralization by soluble CD4 (sCD4). As is the case for the global neutralization resistance phenotype, sCD4 resistance depended upon sequences in the amino-terminal heptad repeat region of gp41 (HR1), as well as on multiple functional interactions within the envelope complex. The functional interactions that determined the resistance included interactions between the variable loop 1 and 2 (V1/V2) region and sequences in or near the CD4 binding site (CD4bs) and with the V3 loop. Additionally, the V3 loop region was found to interact functionally with sequences in the outer domain of gp120, distant from the CD4bs and coreceptor-binding site, as well as with a residue thought to be located centrally in the coreceptor-binding site. These and previous results provide the basis for a model by which functional signals that determine the neutralization resistance, high-infectivity phenotype depend upon interactions occurring across the surface of the gp120 core structure and involving variable loop structures and gp41. This model should be useful in efforts to define epitopes that may be important for primary virus neutralization.

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