Publications by authors named "Shilei Ding"

52 Publications

Live imaging of SARS-CoV-2 infection in mice reveals neutralizing antibodies require Fc function for optimal efficacy.

bioRxiv 2021 Mar 22. Epub 2021 Mar 22.

Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. We visualized sequential spread of virus from the nasal cavity to the lungs followed by systemic spread to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days of infection. In addition to direct neutralization, efficacy required Fc effector functions of NAbs, with contributions from monocytes, neutrophils and natural killer cells, to dampen inflammatory responses and limit immunopathology. Thus, our study highlights the requirement of both Fab and Fc effector functions for an optimal efficacy afforded by NAbs against SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.03.22.436337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010726PMC
March 2021

Major role of IgM in the neutralizing activity of convalescent plasma against SARS-CoV-2.

Cell Rep 2021 03 10;34(9):108790. Epub 2021 Feb 10.

Centre de recherche du CHUM, Montréal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address:

Characterization of the humoral response to SARS-CoV-2, the etiological agent of COVID-19, is essential to help control the infection. The neutralization activity of plasma from patients with COVID-19 decreases rapidly during the first weeks after recovery. However, the specific role of each immunoglobulin isotype in the overall neutralizing capacity is still not well understood. In this study, we select plasma from a cohort of convalescent patients with COVID-19 and selectively deplete immunoglobulin A, M, or G before testing the remaining neutralizing capacity of the depleted plasma. We find that depletion of immunoglobulin M is associated with the most substantial loss of virus neutralization, followed by immunoglobulin G. This observation may help design efficient antibody-based COVID-19 therapies and may also explain the increased susceptibility to SARS-CoV-2 of autoimmune patients receiving therapies that impair the production of immunoglobulin M (IgM).
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http://dx.doi.org/10.1016/j.celrep.2021.108790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874916PMC
March 2021

Stabilizing the HIV-1 envelope glycoprotein State 2A conformation.

J Virol 2020 Dec 9. Epub 2020 Dec 9.

Centre de Recherche du CHUM, Montreal, QC, Canada

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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http://dx.doi.org/10.1128/JVI.01620-20DOI Listing
December 2020

Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles.

Cell Host Microbe 2020 12 13;28(6):880-891.e8. Epub 2020 Nov 13.

Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply single-molecule fluorescence (Förster) resonance energy transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor angiotensin-converting enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate. Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and conformations for immunogen design.
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http://dx.doi.org/10.1016/j.chom.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664471PMC
December 2020

Harnessing Orbital-to-Spin Conversion of Interfacial Orbital Currents for Efficient Spin-Orbit Torques.

Phys Rev Lett 2020 Oct;125(17):177201

Institute of Physics, Johannes Gutenberg University Mainz, Staudingerweg 7, 55128 Mainz, Germany.

Current-induced spin-orbit torques (SOTs) allow for the efficient electrical manipulation of magnetism in spintronic devices. Engineering the SOT efficiency is a key goal that is pursued by maximizing the active interfacial spin accumulation or modulating the nonequilibrium spin density that builds up through the spin Hall and inverse spin galvanic effects. Regardless of the origin, the fundamental requirement for the generation of the current-induced torques is a net spin accumulation. We report on the large enhancement of the SOT efficiency in thulium iron garnet (TmIG)/Pt by capping with a CuO_{x} layer. Considering the weak spin-orbit coupling (SOC) of CuO_{x}, these surprising findings likely result from an orbital current generated at the interface between CuO_{x} and Pt, which is injected into the Pt layer and converted into a spin current by strong SOC. The converted spin current decays across the Pt layer and exerts a "nonlocal" torque on TmIG. This additional torque leads to a maximum colossal enhancement of the SOT efficiency of a factor 16 for 1.5 nm of Pt at room temperature, thus opening a path to increase torques while at the same time offering insights into the underlying physics of orbital transport, which has so far been elusive.
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http://dx.doi.org/10.1103/PhysRevLett.125.177201DOI Listing
October 2020

Antibody Binding to SARS-CoV-2 S Glycoprotein Correlates with but Does Not Predict Neutralization.

Viruses 2020 10 26;12(11). Epub 2020 Oct 26.

Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada.

Convalescent plasma from SARS-CoV-2 infected individuals and monoclonal antibodies were shown to potently neutralize viral and pseudoviral particles carrying the S glycoprotein. However, a non-negligent proportion of plasma samples from infected individuals, as well as S-specific monoclonal antibodies, were reported to be non-neutralizing despite efficient interaction with the S glycoprotein in different biochemical assays using soluble recombinant forms of S or when expressed at the cell surface. How neutralization relates to the binding of S glycoprotein in the context of viral particles remains to be established. Here, we developed a pseudovirus capture assay (VCA) to measure the capacity of plasma samples or antibodies immobilized on ELISA plates to bind to membrane-bound S glycoproteins from SARS-CoV-2 expressed at the surface of lentiviral particles. By performing VCA, ELISA, and neutralization assays, we observed a strong correlation between these parameters. However, while we found that plasma samples unable to capture viral particles did not neutralize, capture did not guarantee neutralization, indicating that the capacity of antibodies to bind to the S glycoprotein at the surface of pseudoviral particles is required but not sufficient to mediate neutralization. Altogether, our results highlight the importance of better understanding the inactivation of S by plasma and neutralizing antibodies.
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http://dx.doi.org/10.3390/v12111214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692607PMC
October 2020

Cross-Sectional Evaluation of Humoral Responses against SARS-CoV-2 Spike.

Cell Rep Med 2020 Oct 30;1(7):100126. Epub 2020 Sep 30.

Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada.

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoproteins of SARS-CoV-2 mediate viral entry and are the main targets for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic, and public health interventions. Here, we perform a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. Most infected individuals elicit anti-Spike antibodies within 2 weeks of the onset of symptoms. The levels of receptor binding domain (RBD)-specific immunoglobulin G (IgG) persist over time, and the levels of anti-RBD IgM decrease after symptom resolution. Although most individuals develop neutralizing antibodies within 2 weeks of infection, the level of neutralizing activity is significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.xcrm.2020.100126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524645PMC
October 2020

Real-time conformational dynamics of SARS-CoV-2 spikes on virus particles.

bioRxiv 2020 Sep 13. Epub 2020 Sep 13.

SARS-CoV-2 spike (S) mediates entry into cells and is critical for vaccine development against COVID-19. S is synthesized as a precursor, processed into S1 and S2 by furin proteases, and activated for fusion when human angiotensin-converting enzyme 2 (hACE2) engages the receptor-binding domain (RBD) and when the N-terminus of S2 is proteolytically processed. Structures of soluble ectodomains and native virus particles have revealed distinct conformations of S, including a closed trimer with all RBD oriented downward, trimers with one or two RBDs up, and hACE2-stabilized conformations with up to three RBD oriented up. Real-time information that connects these structures, however, has been lacking. Here we apply single-molecule Forster Resonance Energy Transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to hACE2, S opens into the hACE2-bound S conformation through at least one on-path intermediate, with trypsin partially activating S. Conformational preferences of convalescent patient plasma and monoclonal antibodies suggest mechanisms of neutralization involving either direct competition with hACE2 for binding to RBD or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and on conformations for immunogen design.
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http://dx.doi.org/10.1101/2020.09.10.286948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491513PMC
September 2020

Antibody binding to SARS-CoV-2 S glycoprotein correlates with, but does not predict neutralization.

bioRxiv 2020 Sep 8. Epub 2020 Sep 8.

Convalescent plasma from SARS-CoV-2 infected individuals and monoclonal antibodies were shown to potently neutralize viral and pseudoviral particles carrying the S glycoprotein. However, a non-negligent proportion of plasma samples from infected individuals as well as S-specific monoclonal antibodies were reported to be non-neutralizing despite efficient interaction with the S glycoprotein in different biochemical assays using soluble recombinant forms of S or when expressed at the cell surface. How neutralization relates to binding of S glycoprotein in the context of viral particles remains to be established. Here we developed a pseudovirus capture assay (VCA) to measure the capacity of plasma samples or antibodies immobilized on ELISA plates to bind to membrane-bound S glycoproteins from SARS-CoV-2 expressed at the surface of lentiviral particles. By performing VCA and neutralization assays we observed a strong correlation between these two parameters. However, while we found that plasma samples unable to capture viral particles did not neutralize, capture did not guarantee neutralization, indicating that the capacity of antibodies to bind to the S glycoprotein at the surface of viral particles is required but not sufficient to mediate neutralization. Altogether, our results highlights the importance of better understanding the inactivation of S by plasma and neutralizing antibodies.
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http://dx.doi.org/10.1101/2020.09.08.287482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491507PMC
September 2020

Defining rules governing recognition and Fc-mediated effector functions to the HIV-1 co-receptor binding site.

BMC Biol 2020 07 21;18(1):91. Epub 2020 Jul 21.

Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814-4712, USA.

Background: The binding of HIV-1 Envelope glycoproteins (Env) to host receptor CD4 exposes vulnerable conserved epitopes within the co-receptor binding site (CoRBS) which are required for the engagement of either CCR5 or CXCR4 co-receptor to allow HIV-1 entry. Antibodies against this region have been implicated in the protection against HIV acquisition in non-human primate (NHP) challenge studies and found to act synergistically with antibodies of other specificities to deliver effective Fc-mediated effector function against HIV-1-infected cells. Here, we describe the structure and function of N12-i2, an antibody isolated from an HIV-1-infected individual, and show how the unique structural features of this antibody allow for its effective Env recognition and Fc-mediated effector function.

Results: N12-i2 binds within the CoRBS utilizing two adjacent sulfo-tyrosines (TYS) for binding, one of which binds to a previously unknown TYS binding pocket formed by gp120 residues of high sequence conservation among HIV-1 strains. Structural alignment with gp120 in complex with the co-receptor CCR5 indicates that the new pocket corresponds to TYS at position 15 of CCR5. In addition, structure-function analysis of N12-i2 and other CoRBS-specific antibodies indicates a link between modes of antibody binding within the CoRBS and Fc-mediated effector activities. The efficiency of antibody-dependent cellular cytotoxicity (ADCC) correlated with both the level of antibody binding and the mode of antibody attachment to the epitope region, specifically with the way the Fc region was oriented relative to the target cell surface. Antibodies with poor Fc access mediated the poorest ADCC whereas those with their Fc region readily accessible for interaction with effector cells mediated the most potent ADCC.

Conclusion: Our data identify a previously unknown binding site for TYS within the assembled CoRBS of the HIV-1 virus. In addition, our combined structural-modeling-functional analyses provide new insights into mechanisms of Fc-effector function of antibodies against HIV-1, in particular, how antibody binding to Env antigen affects the efficiency of ADCC response.
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http://dx.doi.org/10.1186/s12915-020-00819-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374964PMC
July 2020

Cross-sectional evaluation of humoral responses against SARS-CoV-2 Spike.

bioRxiv 2020 Jun 10. Epub 2020 Jun 10.

The SARS-CoV-2 virus is responsible for the current worldwide coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoprotein of SARS-CoV-2 mediates viral entry and is the main target for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic and public health interventions. Here we performed a cross-sectional study on 98 SARS-CoV-2-infected individuals to evaluate humoral responses against the SARS-CoV-2 Spike. The vast majority of infected individuals elicited anti-Spike antibodies within 2 weeks after the onset of symptoms. The levels of receptor-binding domain (RBD)-specific IgG persisted overtime, while the levels of anti-RBD IgM decreased after symptoms resolution. Some of the elicited antibodies cross-reacted with other human coronaviruses in a genus-restrictive manner. While most of individuals developed neutralizing antibodies within the first two weeks of infection, the level of neutralizing activity was significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.06.08.140244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302189PMC
June 2020

Magnetic phase diagram of CrPS and its exchange interaction in contact with NiFe.

J Phys Condens Matter 2020 Jun 18;32(40):405804. Epub 2020 Jun 18.

State Key Laboratory for Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, People's Republic of China.

The magnetic phase diagram of the two-dimensional van der Waals magnet CrPS and the exchange bias effect of CrPS in contact with NiFe film have been investigated. Based on the magnetic measurements, we figure out the relatively low spin-flop field and spin-flip field for CrPS, both of the spin transition phenomena are strongly affected by the temperature. The perpendicular exchange bias effect is studied in CrPS single-crystal flake covered with 5 nm NiFe. Meanwhile, the variation of the cooling field has a great influence on the exchange bias field and coercivity, which is mainly attributed to the competition between the Zeeman energy and the exchange coupling at the interface as well as the formation of the multi-domain state.
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http://dx.doi.org/10.1088/1361-648X/ab9e2dDOI Listing
June 2020

Magnetic Structure and Metamagnetic Transitions in the van der Waals Antiferromagnet CrPS.

Adv Mater 2020 Jul 5;32(28):e2001200. Epub 2020 Jun 5.

State Key Laboratory for Artificial Microstructure & Mesoscopic Physics, School of Physics, Peking University, Beijing, 100871, P. R. China.

In 2D magnets, interlayer exchange coupling is generally weak due to the van der Waals layered structure but it still plays a vital role in stabilizing the long-range magnetic ordering and determining the magnetic properties. Using complementary neutron diffraction, magnetic, and torque measurements, the complete magnetic phase diagram of CrPS crystals is determined. CrPS shows an antiferromagnetic ground state (A-type) formed by out-of-plane ferromagnetic monolayers with interlayer antiferromagnetic coupling along the c axis below T = 38 K. Due to small magnetic anisotropy energy and weak interlayer coupling, the low-field metamagnetic transitions in CrPS that is, a spin-flop transition at ≈0.7 T and a spin-flip transition from antiferromagnetic to ferromagnetic under a relatively low field of 8 T, can be realized for H∥c. Intriguingly, with an inherent in-plane lattice anisotropy, spin-flop-induced moment realignment in CrPS for H∥c is parallel to the quasi-1D chains of CrS octahedra. The peculiar metamagnetic transitions and in-plane anisotropy make few-layer CrPS flakes a fascinating platform for studying 2D magnetism and for exploring prototype device applications in spintronics and optoelectronics.
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http://dx.doi.org/10.1002/adma.202001200DOI Listing
July 2020

Optimization of Small Molecules That Sensitize HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.

ACS Med Chem Lett 2020 Mar 15;11(3):371-378. Epub 2019 Nov 15.

Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

With approximately 37 million people living with HIV worldwide and an estimated 2 million new infections reported each year, the need to derive novel strategies aimed at eradicating HIV-1 infection remains a critical worldwide challenge. One potential strategy would involve eliminating infected cells via antibody-dependent cellular cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to conceal epitopes located in its envelope glycoprotein (Env) that are recognized by ADCC-mediating antibodies present in sera from HIV-1 infected individuals. Our aim is to circumvent this evasion via the development of small molecules that expose relevant anti-Env epitopes and sensitize HIV-1 infected cells to ADCC. Rapid elaboration of an initial screening hit using parallel synthesis and structure-based optimization has led to the development of potent small molecules that elicit this humoral response. Efforts to increase the ADCC activity of this class of small molecules with the aim of increasing their therapeutic potential was based on our recent cocrystal structures with gp120 core.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074219PMC
March 2020

A New Family of Small-Molecule CD4-Mimetic Compounds Contacts Highly Conserved Aspartic Acid 368 of HIV-1 gp120 and Mediates Antibody-Dependent Cellular Cytotoxicity.

J Virol 2019 12 26;93(24). Epub 2019 Nov 26.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The "closed" conformation of Env is resistant to nonneutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have a limited capacity to inhibit virus infection directly but are able to sensitize viral particles to neutralization by otherwise nonneutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly conserved D368 residue, making them attractive scaffolds for drug development. HIV-1 has evolved multiple strategies to avoid humoral responses. One efficient mechanism is to keep its envelope glycoprotein (Env) in its "closed" conformation. Here, we report on a new family of small molecules that are able to "open up" Env, thus exposing vulnerable epitopes. This new family of molecules binds in the Phe43 cavity and contacts the highly conserved D368 residue. The structural and biological attributes of molecules of this family make them good candidates for drug development.
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http://dx.doi.org/10.1128/JVI.01325-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880173PMC
December 2019

CD4 Incorporation into HIV-1 Viral Particles Exposes Envelope Epitopes Recognized by CD4-Induced Antibodies.

J Virol 2019 11 29;93(22). Epub 2019 Oct 29.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

CD4 downregulation on infected cells is a highly conserved function of primate lentiviruses. It has been shown to positively impact viral replication by a variety of mechanisms, including enhanced viral release and infectivity, decrease of cell reinfection, and protection from antibody-dependent cellular cytotoxicity (ADCC), which is often mediated by antibodies that require CD4 to change envelope (Env) conformation. Here, we report that incorporation of CD4 into HIV-1 viral particles affects Env conformation resulting in the exposure of occluded epitopes recognized by CD4-induced antibodies. This translates into enhanced neutralization susceptibility by these otherwise nonneutralizing antibodies but is prevented by the HIV-1 Nef accessory protein. Altogether, these findings suggest that another functional consequence of Nef-mediated CD4 downregulation is the protection of viral particles from neutralization by commonly elicited CD4-induced antibodies. It has been well established that Env-CD4 complexes expose epitopes recognized by commonly elicited CD4-induced antibodies at the surface of HIV-1-infected cells, rendering them vulnerable to ADCC responses. Here, we show that CD4 incorporation has a profound impact on Env conformation at the surface of viral particles. Incorporated CD4 exposes CD4-induced epitopes on Env, rendering HIV-1 susceptible to neutralization by otherwise nonneutralizing antibodies.
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http://dx.doi.org/10.1128/JVI.01403-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819941PMC
November 2019

Spin switching temperature modulated by the magnetic field and spontaneous exchange bias effect in single crystal SmFeO.

J Phys Condens Matter 2019 Oct 4;31(43):435801. Epub 2019 Jul 4.

State Key Laboratory for Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, People's Republic of China.

The spin switching and exchange bias effect were investigated in the rare earth orthoferrite SmFeO composed of two antiferromagnetically coupled sublattices Sm and Fe with canted ferromagnetic moments and a temperature induced spin switching in single crystal SmFeO was observed. The spin switching temperature was found to be modulated by exerting different magnetic fields below the compensation temperature ([Formula: see text]). This effect could be explained as the changes of energy barrier related to the magnetization direction under different magnetic fields. In the meantime, the coercivity displayed strong dependence on the maximum applied magnetic fields in the hysteresis measurement. In addition, spontaneous exchange bias effect (EB) was observed with the largest EB field value of 1.2 T, and the EB field changed its sign across the compensation point. Our results indicate that the magnetic properties of SmFeO can be strongly affected and controlled by the temperature or the applied magnetic field during the measurement process, and it might lead to novel applications in magneto-optics, ultrafast switching, and magnetic sensing devices.
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http://dx.doi.org/10.1088/1361-648X/ab2f51DOI Listing
October 2019

Immune Correlates of Disease Progression in Linked HIV-1 Infection.

Front Immunol 2019 14;10:1062. Epub 2019 May 14.

Department of Pathology, New York University School of Medicine, New York, NY, United States.

Genetic and immunologic analyses of epidemiologically-linked HIV transmission enable insights into the impact of immune responses on clinical outcomes. Human vaccine trials and animal studies of HIV-1 infection have suggested immune correlates of protection; however, their role in natural infection in terms of protection from disease progression is mostly unknown. Four HIV-1 Cameroonian individuals, three of them epidemiologically-linked in a polygamous heterosexual relationship and one incidence-matched case, were studied over 15 years for heterologous and cross-neutralizing antibody responses, antibody binding, IgA/IgG levels, antibody-dependent cellular cytotoxicity (ADCC) against cells expressing wild-type or CD4-bound Env, viral evolution, Env epitopes, and host factors including HLA-I alleles. Despite viral infection with related strains, the members of the transmission cluster experienced contrasting clinical outcomes including cases of rapid progression and long-term non-progression in the absence of strongly protective HLA-I or CCR5Δ32 alleles. Slower progression and higher CD4/CD8 ratios were associated with enhanced IgG antibody binding to native Env and stronger V1V2 antibody binding responses in the presence of viruses with residue K169 in V2. ADCC against cells expressing Env in the CD4-bound conformation in combination with low Env-specific IgA/IgG ratios correlated with better clinical outcome. This data set highlights for the first time that V1V2-directed antibody responses and ADCC against cells expressing open, CD4-exposed Env, in the presence of low plasma IgA/IgG ratios, can correlate with clinical outcome in natural infection. These parameters are comparable to the major correlates of protection, identified in the RV144 vaccine trial; thus, they may also modulate the rate of clinical progression once infected. The findings illustrate the potential of immune correlate analysis in natural infection to guide vaccine development.
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http://dx.doi.org/10.3389/fimmu.2019.01062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527802PMC
August 2020

An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity.

Cell Host Microbe 2019 Apr;25(4):578-587.e5

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA. Electronic address:

The HIV-1 envelope glycoprotein (Env) (gp120-gp41) is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.
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http://dx.doi.org/10.1016/j.chom.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592637PMC
April 2019

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

J Virol 2019 06 15;93(11). Epub 2019 May 15.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

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. 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.
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http://dx.doi.org/10.1128/JVI.00293-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532100PMC
June 2019

Identification of HIV gp41-specific antibodies that mediate killing of infected cells.

PLoS Pathog 2019 02 19;15(2):e1007572. Epub 2019 Feb 19.

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA, United States of America.

Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine.
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http://dx.doi.org/10.1371/journal.ppat.1007572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396944PMC
February 2019

CD4 receptor diversity in chimpanzees protects against SIV infection.

Proc Natl Acad Sci U S A 2019 02 4;116(8):3229-3238. Epub 2019 Feb 4.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4 T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.
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http://dx.doi.org/10.1073/pnas.1821197116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386711PMC
February 2019

Synthesis of a magnetic polystyrene-based cation-exchange resin and its utilization for the efficient removal of cadmium (II).

Water Sci Technol 2018 Jul;2017(3):770-781

School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China E-mail:

A magnetic cation-exchange resin (MCER) was prepared by copolymerization of oleic acid-grafted magnetite with styrene, divinylbenzene (DVB), and triallylisocyanurate (TAIC) for removing Cd(II) from wastewater. A non-magnetic cation-exchange polystyrene resin (CEPR) was also prepared as a reference. Structural and morphological analyses revealed that the MCER and CEPR were mesoporous microspheres; the MCER contained about 25% FeO. The influence of temperature, pH, contact time, and the initial concentration of Cd(II) on the adsorption of Cd(II) was investigated. The maximum adsorption capacity of the MCER reached 88.56 mg/g, which was achieved at 343 K using a Cd(II) initial concentration of 200 mg/L. The adsorption processes attained equilibrium within 120 min for the MCER and 300 min for the CEPR, and were well described by a pseudo-second-order kinetic model. Furthermore, the equilibrium adsorption data fitted the Freundlich isotherm model better than the Langmuir model. The superior magnetic response and regeneration of the MCER make it a good candidate as an adsorbent for removing Cd(II) from wastewater.
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http://dx.doi.org/10.2166/wst.2018.239DOI Listing
July 2018

A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge.

Nat Commun 2018 06 18;9(1):2363. Epub 2018 Jun 18.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

The envelope glycoprotein (Env) trimer ((gp120/gp41)) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.
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http://dx.doi.org/10.1038/s41467-018-04758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006336PMC
June 2018

Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses.

mBio 2018 03 20;9(2). Epub 2018 Mar 20.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a "closed" conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in cultures or samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands. Emerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate ADCC. Here, we performed a side-by-side comparison of different methods currently being used in the field to measure ADCC responses to HIV-1. We found that assays which are unable to differentiate virus-infected from uninfected cells greatly overestimate ADCC responses mediated by antibodies to CD4i epitopes and underestimate responses mediated by broadly neutralizing antibodies (bNAbs). Our results strongly argue for the use of assays that measure ADCC against HIV-1-infected cells expressing physiologically relevant conformations of Env to evaluate correlates of protection in vaccine trials.
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http://dx.doi.org/10.1128/mBio.00358-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874913PMC
March 2018

Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals.

Virology 2018 02 15;515:38-45. Epub 2017 Dec 15.

Centre de Recherche du CHUM, QC, Canada H2X 0A9; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada H2X 0A9; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada H3A 2B4. Electronic address:

Recent analysis of HIV-1 envelope glycoproteins (Env) dynamics showed that the unliganded Env trimer can potentially sample three conformations: a metastable "closed" conformation (State 1), an "open" CD4-bound conformation (State 3), and an intermediate "partially open" conformation (State 2). HIV-1 evolved several mechanisms to avoid "opening" its Env in order to evade immune responses such as antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets Envs in the CD4-bound conformation on the surface of infected cells. Here we took advantage of a well-characterized single-residue change in the gp120 trimer association domain to modify Env conformation and evaluate its impact on ADCC responses. We found that cells infected with viruses expressing Env stabilized in States 2/3 become highly susceptible to ADCC responses by sera from HIV-1-infected individuals. Our results indicate that the conformations spontaneously sampled by the Env trimer at the surface of infected cells has a significant impact on ADCC responses.
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http://dx.doi.org/10.1016/j.virol.2017.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843759PMC
February 2018

Impact of HIV-1 Envelope Conformation on ADCC Responses.

Trends Microbiol 2018 04 20;26(4):253-265. Epub 2017 Nov 20.

Centre de Recherche du CHUM, Montreal, QC, H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada. Electronic address:

HIV-1 envelope glycoproteins (Env) represent the only virus-specific antigen exposed at the surface of infected cells. In its unliganded form, Env from primary viruses samples a 'closed' conformation (State 1), which is preferentially recognized by broadly neutralizing antibodies (bNAbs). CD4 engagement drives Env into an intermediate 'partially open' (State 2) and then into the 'open' CD4-bound conformation (State 3). Emerging evidence suggests a link between Env conformation and Ab-dependent cellular cytotoxicity (ADCC). HIV-1-infected cells exposing Env in the CD4-bound conformation are susceptible to ADCC mediated by CD4-induced Abs and HIV+sera. Cells exposing State 1 Env are susceptible to ADCC mediated by bNAbs. Here, we discuss how Env conformation affects ADCC responses and in vitro measurements.
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http://dx.doi.org/10.1016/j.tim.2017.10.007DOI Listing
April 2018

Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region.

Structure 2017 11 19;25(11):1719-1731.e4. Epub 2017 Oct 19.

Division of Vaccine Research, Institute of Human Virology, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA. Electronic address:

Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal "eighth strand" of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered β-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system.
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http://dx.doi.org/10.1016/j.str.2017.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677539PMC
November 2017

Unlocking HIV-1 Env: implications for antibody attack.

AIDS Res Ther 2017 Sep 12;14(1):42. Epub 2017 Sep 12.

Centre de Recherche du CHUM (CRCHUM), 900 St-Denis Street, Tour Viger, Montréal, QC, H2X 0A9, Canada.

Collective evidence supporting a role of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in controlling HIV-1 transmission and disease progression emerged in the last few years. Non-neutralizing antibodies (nnAbs) recognizing conserved CD4-induced epitopes on Env and able to mediate potent ADCC against HIV-1-infected cells exposing Env in its CD4-bound conformation have been shown to be present in some RV144 vaccinees and most HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to decrease exposure of this Env conformation by downregulating CD4 and by limiting the overall amount of cell-surface Env. In this review, we will summarize our contribution to this rapidly evolving field, discuss how structural properties of HIV-1 Env might have contributed to the modest efficacy of the RV144 trial and how we recently used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected cells to ADCC mediated by easy to elicit nnAbs.
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http://dx.doi.org/10.1186/s12981-017-0168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594528PMC
September 2017

BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity.

J Virol 2017 06 12;91(11). Epub 2017 May 12.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication.
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http://dx.doi.org/10.1128/JVI.00219-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432882PMC
June 2017