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  1. Article: Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.

    Roederer, Alex L / Cao, Yi / Denis, Kerri St / Sheehan, Maegan L / Li, Chia Jung / Lam, Evan C / Gregory, David J / Poznansky, Mark C / Iafrate, A John / Canaday, David H / Gravenstein, Stefan / Garcia-Beltran, Wilfredo F / Balazs, Alejandro B

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 ... ...

    Abstract Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera. However, progressive loss of neutralization was observed across newer variants, irrespective of vaccine doses. Importantly, an updated XBB.1.5 booster significantly increased titers against newer variants but not JN.1. These findings demonstrate that seasonal boosters improve titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating the need for novel approaches to adequately control SARS-CoV-2 transmission.
    Language English
    Publishing date 2024-03-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.05.24303815
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Natural Killer Cell Interactions with Classical and Non-Classical Human Leukocyte Antigen Class I in HIV-1 Infection.

    Hölzemer, Angelique / Garcia-Beltran, Wilfredo F / Altfeld, Marcus

    Frontiers in immunology

    2017  Volume 8, Page(s) 1496

    Abstract: ... the more conserved, non-classical HLA-I molecules HLA-E, -G, and -F. In this review, we will focus ...

    Abstract Natural killer (NK) cells are effector lymphocytes of the innate immune system that are able to mount a multifaceted antiviral response within hours following infection. This is achieved through an array of cell surface receptors surveilling host cells for alterations in human leukocyte antigen class I (HLA-I) expression and other ligands as signs of viral infection, malignant transformation, and cellular stress. This interaction between HLA-I ligands and NK-cell receptor is not only important for recognition of diseased cells but also mediates tuning of NK-cell-effector functions. HIV-1 alters the expression of HLA-I ligands on infected cells, rendering them susceptible to NK cell-mediated killing. However, over the past years, various HIV-1 evasion strategies have been discovered to target NK-cell-receptor ligands and allow the virus to escape from NK cell-mediated immunity. While studies have been mainly focusing on the role of polymorphic HLA-A, -B, and -C molecules, less is known about how HIV-1 affects the more conserved, non-classical HLA-I molecules HLA-E, -G, and -F. In this review, we will focus on the recent progress in understanding the role of non-classical HLA-I ligands in NK cell-mediated recognition of HIV-1-infected cells.
    Language English
    Publishing date 2017-11-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2017.01496
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

    Zhang, Fengwen / Zang, Trinity M / Stevenson, Eva M / Lei, Xiao / Copertino, Dennis C / Mota, Talia M / Boucau, Julie / Garcia-Beltran, Wilfredo F / Jones, R Brad / Bieniasz, Paul D

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 41, Page(s) e2209042119

    Abstract: Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to ... ...

    Abstract Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8
    MeSH term(s) Amino Acids ; Antigen Presentation ; CD8-Positive T-Lymphocytes/immunology ; COVID-19/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; Major Histocompatibility Complex ; Peptides ; SARS-CoV-2 ; Viral Proteins/immunology
    Chemical Substances Amino Acids ; Histocompatibility Antigens Class I ; ORF7a protein, SARS-CoV-2 ; Peptides ; Viral Proteins
    Language English
    Publishing date 2022-09-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2209042119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A Genome-Wide CRISPR/Cas9-Based Screen Identifies Heparan Sulfate Proteoglycans as Ligands of Killer-Cell Immunoglobulin-Like Receptors.

    Klein, Klara / Hölzemer, Angelique / Wang, Tim / Kim, Tae-Eun / Dugan, Haley L / Jost, Stephanie / Altfeld, Marcus / Garcia-Beltran, Wilfredo F

    Frontiers in immunology

    2021  Volume 12, Page(s) 798235

    Abstract: ... to HLA-F. In this study, we assessed the ligand binding profile of KIR3DS1 to cell lines using Fc fusion ...

    Abstract While human leukocyte antigen (HLA) and HLA-like proteins comprise an overwhelming majority of known ligands for NK-cell receptors, the interactions of NK-cell receptors with non-conventional ligands, particularly carbohydrate antigens, is less well described. We previously found through a bead-based HLA screen that KIR3DS1, a formerly orphan member of the killer-cell immunoglobulin-like receptor (KIR) family, binds to HLA-F. In this study, we assessed the ligand binding profile of KIR3DS1 to cell lines using Fc fusion constructs, and discovered that KIR3DS1-Fc exhibited binding to several human cell lines including ones devoid of HLA. To identify these non-HLA ligands, we developed a magnetic enrichment-based genome-wide CRISPR/Cas9 knock-out screen approach, and identified enzymes involved in the biosynthesis of heparan sulfate as crucial for the binding of KIR3DS1-Fc to K562 cells. This interaction between KIR3DS1 and heparan sulfate was confirmed
    MeSH term(s) CRISPR-Associated Protein 9/metabolism ; CRISPR-Cas Systems ; Genome-Wide Association Study ; Heparan Sulfate Proteoglycans/agonists ; Humans ; K562 Cells ; Killer Cells, Natural/immunology ; Ligands ; Receptors, KIR/agonists ; Receptors, KIR3DS1/metabolism ; Signal Transduction
    Chemical Substances Heparan Sulfate Proteoglycans ; KIR3DS1 protein, human ; Ligands ; Receptors, KIR ; Receptors, KIR3DS1 ; CRISPR-Associated Protein 9 (EC 3.1.-)
    Language English
    Publishing date 2021-11-30
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.798235
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Lectin Fingerprinting Distinguishes Antibody Neutralization in SARS-CoV-2.

    Wuo, Michael G / Dugan, Amanda E / Halim, Melanie / Hauser, Blake M / Feldman, Jared / Caradonna, Timothy M / Zhang, Shuting / Pepi, Lauren E / Atyeo, Caroline / Fischinger, Stephanie / Alter, Galit / Garcia-Beltran, Wilfredo F / Azadi, Parastoo / Hung, Deb / Schmidt, Aaron G / Kiessling, Laura L

    ACS central science

    2023  Volume 9, Issue 5, Page(s) 947–956

    Abstract: Enveloped viruses co-opt host glycosylation pathways to decorate their surface proteins. As viruses evolve, emerging strains can modify their glycosylation patterns to influence host interactions and subvert immune recognition. Still, changes in viral ... ...

    Abstract Enveloped viruses co-opt host glycosylation pathways to decorate their surface proteins. As viruses evolve, emerging strains can modify their glycosylation patterns to influence host interactions and subvert immune recognition. Still, changes in viral glycosylation or their impact on antibody protection cannot be predicted from genomic sequences alone. Using the highly glycosylated SARS-CoV-2 Spike protein as a model system, we present a lectin fingerprinting method that rapidly reports on changes in variant glycosylation state, which are linked to antibody neutralization. In the presence of antibodies or convalescent and vaccinated patient sera, unique lectin fingerprints emerge that distinguish neutralizing versus non-neutralizing antibodies. This information could not be inferred from direct binding interactions between antibodies and the Spike receptor-binding domain (RBD) binding data alone. Comparative glycoproteomics of the Spike RBD of wild-type (Wuhan-Hu-1) and Delta (B.1.617.2) variants reveal O-glycosylation differences as a key determinant of immune recognition differences. These data underscore the interplay between viral glycosylation and immune recognition and reveal lectin fingerprinting to be a rapid, sensitive, and high-throughput assay to distinguish the neutralization potential of antibodies that target critical viral glycoproteins.
    Language English
    Publishing date 2023-05-10
    Publishing country United States
    Document type Journal Article
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.2c01471
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

    Zhang, Fengwen / Zang, Trinity / Stevenson, Eva M / Lei, Xiao / Copertino, Dennis C / Mota, Talia M / Boucau, Julie / Garcia-Beltran, Wilfredo F / Jones, R Brad / Bieniasz, Paul D

    bioRxiv : the preprint server for biology

    2022  

    Abstract: ... from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is ...

    Abstract Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2022.05.25.493467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer.

    Naranbhai, Vivek / St Denis, Kerri J / Lam, Evan C / Ofoman, Onosereme / Garcia-Beltran, Wilfredo F / Mairena, Cristhian B / Bhan, Atul K / Gainor, Justin F / Balazs, Alejandro B / Iafrate, A John

    Cancer cell

    2022  Volume 40, Issue 1, Page(s) 103–108.e2

    Abstract: Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses ... ...

    Abstract Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants.
    MeSH term(s) Aged ; Aging/immunology ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Viral/biosynthesis ; Antigens, Viral/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; Female ; Humans ; Immunization, Secondary ; Immunocompromised Host ; Immunogenicity, Vaccine ; In Vitro Techniques ; Male ; Middle Aged ; Neoplasms/immunology ; Neoplasms/therapy ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Viral Load
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Antigens, Viral ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-01-05
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2021.12.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: HIV-1 Nef-mediated downregulation of CD155 results in viral restriction by KIR2DL5+ NK cells.

    Fittje, Pia / Hœlzemer, Angelique / Garcia-Beltran, Wilfredo F / Vollmers, Sarah / Niehrs, Annika / Hagemann, Kerri / Martrus, Glòria / Körner, Christian / Kirchhoff, Frank / Sauter, Daniel / Altfeld, Marcus

    PLoS pathogens

    2022  Volume 18, Issue 6, Page(s) e1010572

    Abstract: Antiviral NK cell activity is regulated through the interaction of activating and inhibitory NK cell receptors with their ligands on infected cells. HLA class I molecules serve as ligands for most killer cell immunoglobulin-like receptors (KIRs), but no ... ...

    Abstract Antiviral NK cell activity is regulated through the interaction of activating and inhibitory NK cell receptors with their ligands on infected cells. HLA class I molecules serve as ligands for most killer cell immunoglobulin-like receptors (KIRs), but no HLA class I ligands for the inhibitory NK cell receptor KIR2DL5 have been identified to date. Using a NK cell receptor/ligand screening approach, we observed no strong binding of KIR2DL5 to HLA class I or class II molecules, but confirmed that KIR2DL5 binds to the poliovirus receptor (PVR, CD155). Functional studies using primary human NK cells revealed a significantly decreased degranulation of KIR2DL5+ NK cells in response to CD155-expressing target cells. We subsequently investigated the role of KIR2DL5/CD155 interactions in HIV-1 infection, and showed that multiple HIV-1 strains significantly decreased CD155 expression levels on HIV-1-infected primary human CD4+ T cells via a Nef-dependent mechanism. Co-culture of NK cells with HIV-1-infected CD4+ T cells revealed enhanced anti-viral activity of KIR2DL5+ NK cells against wild-type versus Nef-deficient viruses, indicating that HIV-1-mediated downregulation of CD155 renders infected cells more susceptible to recognition by KIR2DL5+ NK cells. These data show that CD155 suppresses the antiviral activity of KIR2DL5+ NK cells and is downmodulated by HIV-1 Nef protein as potential trade-off counteracting activating NK cell ligands, demonstrating the ability of NK cells to counteract immune escape mechanisms employed by HIV-1.
    MeSH term(s) Antiviral Agents/metabolism ; Down-Regulation ; HIV Infections ; HIV Seropositivity ; HIV-1 ; Humans ; Killer Cells, Natural ; Ligands ; Receptors, Natural Killer Cell/metabolism ; Receptors, Virus ; nef Gene Products, Human Immunodeficiency Virus/genetics ; nef Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances Antiviral Agents ; Ligands ; Receptors, Natural Killer Cell ; Receptors, Virus ; nef Gene Products, Human Immunodeficiency Virus ; nef protein, Human immunodeficiency virus 1 ; nef protein, Human immunodeficiency virus 2 ; poliovirus receptor
    Language English
    Publishing date 2022-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010572
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity

    Roederer, Alex L. / Cao, Yi / St. Denis, Kerri / Sheehan, Maegan L. / Li, Chia Jung / Lam, Evan C. / Gregory, David J. / Poznansky, Mark C. / Iafrate, A. John / Canaday, David H. / Gravenstein, Stefan / Garcia-Beltran, Wilfredo F. / Balazs, Alejandro B.

    medRxiv

    Abstract: Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 ... ...

    Abstract Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera. However, progressive loss of neutralization was observed across newer variants, irrespective of vaccine doses. Importantly, an updated XBB.1.5 booster significantly increased titers against newer variants but not JN.1. These findings demonstrate that seasonal boosters improve titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating the need for novel approaches to adequately control SARS-CoV-2 transmission.
    Keywords covid19
    Language English
    Publishing date 2024-03-07
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2024.03.05.24303815
    Database COVID19

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  10. Article ; Online: Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses.

    Hartmann, Jordan A / Cardoso, Marcella R / Talarico, Maria Cecilia Ramiro / Kenney, Devin J / Leone, Madison R / Reese, Dagny C / Turcinovic, Jacquelyn / O'Connell, Aoife K / Gertje, Hans P / Marino, Caitlin / Ojeda, Pedro E / De Paula, Erich V / Orsi, Fernanda A / Velloso, Licio Augusto / Cafiero, Thomas R / Connor, John H / Ploss, Alexander / Hoelzemer, Angelique / Carrington, Mary /
    Barczak, Amy K / Crossland, Nicholas A / Douam, Florian / Boucau, Julie / Garcia-Beltran, Wilfredo F

    Cell

    2024  

    Abstract: SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an ... ...

    Abstract SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.
    Language English
    Publishing date 2024-04-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2024.03.026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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