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 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 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 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.

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 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 Apoptosis of Bystander T Cells Induced by Human Immunodeficiency Virus Type 1 with Increased Envelope/Receptor Affinity and Coreceptor Binding Site Exposure

2004 ◽  
Vol 78 (9) ◽  
pp. 4541-4551 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Chengsheng Zhang ◽  
Paul R. Gorry ◽  
Keith Peden ◽  
Dominique Schols ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Membrane Fusion ◽  
Binding Site ◽  
Receptor Affinity ◽  
Coreceptor Binding ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Coreceptor Binding Site

ABSTRACT Apoptosis of uninfected bystander CD4+ T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) pathogenesis. The viral and host mechanisms that lead to bystander apoptosis are not well understood. To investigate properties of the viral envelope glycoproteins (Env proteins) that influence the ability of HIV-1 to induce bystander apoptosis, we used molecularly cloned viruses that differ only in specific amino acids in Env. The ability of these strains to induce bystander apoptosis was tested in herpesvirus saimiri-immortalized primary CD4+ T cells (CD4/HVS), which resemble activated primary T cells. Changes in Env that increase affinity for CD4 or CCR5 or increase coreceptor binding site exposure enhanced the capacity of HIV-1 to induce bystander apoptosis following viral infection or exposure to nonreplicating virions. Apoptosis induced by HIV-1 virions was inhibited by CD4, CXCR4, and CCR5 antibodies or by the CXCR4 inhibitor AMD3100, but not the fusion inhibitor T20. HIV-1 virions with mutant Envs that bind CXCR4 but are defective for CD4 binding or membrane fusion induced apoptosis, whereas CXCR4 binding-defective mutants did not. These results demonstrate that HIV-1 virions induce apoptosis through a CXCR4- or CCR5-dependent pathway that does not require Env/CD4 signaling or membrane fusion and suggest that HIV-1 variants with increased envelope/receptor affinity or coreceptor binding site exposure may promote T-cell depletion in vivo by accelerating bystander cell death.

scholarly journals Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma

2008 ◽  
Vol 83 (3) ◽  
pp. 1240-1259 ◽  
Author(s):  
Katie L. Davis ◽  
Frederic Bibollet-Ruche ◽  
Hui Li ◽  
Julie M. Decker ◽  
Olaf Kutsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Monoclonal Antibodies ◽  
Binding Site ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
High Titer ◽  
Second Primary ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Deciphering antibody specificities that constrain human immunodeficiency virus type 1 (HIV-1) envelope (Env) diversity, limit virus replication, and contribute to neutralization breadth and potency is an important goal of current HIV/AIDS vaccine research. Transplantation of discrete HIV-1 neutralizing epitopes into HIV-2 scaffolds may provide a sensitive, biologically functional context by which to quantify specific antibody reactivities even in complex sera. Here, we describe a novel HIV-2 proviral scaffold (pHIV-2KR.X7) into which we substituted the complete variable region 3 (V3) of the env gene of HIV-1YU2 or HIV-1Ccon to yield the chimeric proviruses pHIV-2KR.X7 YU2 V3 and pHIV-2KR.X7 Ccon V3. These HIV-2/HIV-1 chimeras were replication competent and sensitive to selective pharmacological inhibitors of virus entry. V3 chimeric viruses were resistant to neutralization by HIV-1 monoclonal antibodies directed against the CD4 binding site, coreceptor binding site, and gp41 membrane proximal external region but exhibited striking sensitivity to HIV-1 V3-specific monoclonal antibodies, 447-52D and F425 B4e8 (50% inhibitory concentration of [IC50] <0.005 μg/ml for each). Plasma specimens from 11 HIV-1 clade B- and 10 HIV-1 clade C-infected subjects showed no neutralizing activity against HIV-2 but exhibited high-titer V3-specific neutralization against both HIV-2/HIV-1 V3 chimeras with IC50 measurements ranging from 1:50 to greater than 1:40,000. Neutralization titers of B clade plasmas were as much as 1,000-fold lower when tested against the primary HIV-1YU2 virus than with the HIV-2KR.X7 YU2 V3 chimera, demonstrating highly effective shielding of V3 epitopes in the native Env trimer. This finding was replicated using a second primary HIV-1 strain (HIV-1BORI) and the corresponding HIV-2KR.X7 BORI V3 chimera. We conclude that V3 is highly immunogenic in vivo, eliciting antibodies with substantial breadth of reactivity and neutralizing potential. These antibodies constrain HIV-1 Env to a structure(s) in which V3 epitopes are concealed prior to CD4 engagement but do not otherwise contribute to neutralization breadth and potency against most primary virus strains. Triggering of the viral spike to reveal V3 epitopes may be required if V3 immunogens are to be components of an effective HIV-1 vaccine.

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 Characterization of a Human Immunodeficiency Virus Type 1 V3 Deletion Mutation That Confers Resistance to CCR5 Inhibitors and the Ability To Use Aplaviroc-Bound Receptor

2009 ◽  
Vol 83 (8) ◽  
pp. 3798-3809 ◽  
Author(s):  
Katrina M. Nolan ◽  
Gregory Q. Del Prete ◽  
Andrea P. O. Jordan ◽  
Beth Haggarty ◽  
Josephine Romano ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Monoclonal Antibodies ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Entry Inhibitors ◽  
Coreceptor Binding ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) V3 loop is essential for coreceptor binding and principally determines tropism for the CCR5 and CXCR4 coreceptors. Using the dual-tropic virus HIV-1R3A, we previously made an extensive panel of V3 deletions and identified subdomains within V3 that could differentially mediate R5 and X4 tropism. A deletion of residues 9 to 12 on the N-terminal side of the V3 stem ablated X4 tropism while leaving R5 tropism intact. This mutation also resulted in complete resistance to several small-molecule CCR5 inhibitors. Here, we extend these studies to further characterize a variant of this mutant, Δ9-12a, adapted for growth in CCR5+ SupT1 cells. Studies using coreceptor chimeras, monoclonal antibodies directed against the CCR5 amino terminus (NT) and extracellular loops, and CCR5 point mutants revealed that, relative to parental R3A, R5-tropic Δ9-12a was more dependent on the CCR5 NT, a region that contacts the gp120 bridging sheet and V3 base. Neutralization sensitivity assays showed that, compared to parental R3A, Δ9-12a was more sensitive to monoclonal antibodies b12, 4E10, and 2G12. Finally, cross-antagonism assays showed that Δ9-12a could use aplaviroc-bound CCR5 for entry. These studies indicate that increased dependence on the CCR5 NT represents a mechanism by which HIV envelopes acquire resistance to CCR5 antagonists and may have more general implications for mechanisms of drug resistance that arise in vivo. In addition, envelopes such as Δ9-12a may be useful for developing new entry inhibitors that target the interaction of gp120 and the CCR5 NT.

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.

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