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Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women

Transmission of HIV across the mucosal surface of the female reproductive tract to engage subepithelial CD4-positive T cells is not fully understood. Cervical epithelial cells express complement receptor 3 (CR3) (integrin α(M)β(2) or CD11b/CD18). In women, the bacterium Neisseria gonorrhoeae uses CR...

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Autores principales: Day, Christopher J., Hardison, Rachael L., Spillings, Belinda L., Poole, Jessica, Jurcisek, Joseph A., Mak, Johnson, Jennings, Michael P., Edwards, Jennifer L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749410/
https://www.ncbi.nlm.nih.gov/pubmed/35012346
http://dx.doi.org/10.1128/mbio.02177-21
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author Day, Christopher J.
Hardison, Rachael L.
Spillings, Belinda L.
Poole, Jessica
Jurcisek, Joseph A.
Mak, Johnson
Jennings, Michael P.
Edwards, Jennifer L.
author_facet Day, Christopher J.
Hardison, Rachael L.
Spillings, Belinda L.
Poole, Jessica
Jurcisek, Joseph A.
Mak, Johnson
Jennings, Michael P.
Edwards, Jennifer L.
author_sort Day, Christopher J.
collection PubMed
description Transmission of HIV across the mucosal surface of the female reproductive tract to engage subepithelial CD4-positive T cells is not fully understood. Cervical epithelial cells express complement receptor 3 (CR3) (integrin α(M)β(2) or CD11b/CD18). In women, the bacterium Neisseria gonorrhoeae uses CR3 to invade the cervical epithelia to cause cervicitis. We hypothesized that HIV may also use CR3 to transcytose across the cervical epithelia. Here, we show that HIV-1 strains bound with high affinity to recombinant CR3 in biophysical assays. HIV-1 bound CR3 via the I-domain region of the CR3 alpha subunit, CD11b, and binding was dependent on HIV-1 N-linked glycans. Mannosylated glycans on the HIV surface were a high-affinity ligand for the I-domain. Man5 pentasaccharide, representative of HIV N-glycans, could compete with HIV-1 for CR3 binding. Using cellular assays, we show that HIV bound to CHO cells by a CR3-dependent mechanism. Antibodies to the CR3 I-domain or to the HIV-1 envelope glycoprotein blocked the binding of HIV-1 to primary human cervical epithelial (Pex) cells, indicating that CR3 was necessary and sufficient for HIV-1 adherence to Pex cells. Using Pex cells in a Transwell model system, we show that, following transcytosis across an intact Pex cell monolayer, HIV-1 is able to infect TZM-bl reporter cells. Targeting the HIV-CR3 interaction using antibodies, mannose-binding lectins, or CR3-binding small-molecule drugs blocked HIV transcytosis. These studies indicate that CR3/Pex may constitute an efficient pathway for HIV-1 transmission in women and also demonstrate strategies that may prevent transmission via this pathway.
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spelling pubmed-87494102022-01-24 Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women Day, Christopher J. Hardison, Rachael L. Spillings, Belinda L. Poole, Jessica Jurcisek, Joseph A. Mak, Johnson Jennings, Michael P. Edwards, Jennifer L. mBio Research Article Transmission of HIV across the mucosal surface of the female reproductive tract to engage subepithelial CD4-positive T cells is not fully understood. Cervical epithelial cells express complement receptor 3 (CR3) (integrin α(M)β(2) or CD11b/CD18). In women, the bacterium Neisseria gonorrhoeae uses CR3 to invade the cervical epithelia to cause cervicitis. We hypothesized that HIV may also use CR3 to transcytose across the cervical epithelia. Here, we show that HIV-1 strains bound with high affinity to recombinant CR3 in biophysical assays. HIV-1 bound CR3 via the I-domain region of the CR3 alpha subunit, CD11b, and binding was dependent on HIV-1 N-linked glycans. Mannosylated glycans on the HIV surface were a high-affinity ligand for the I-domain. Man5 pentasaccharide, representative of HIV N-glycans, could compete with HIV-1 for CR3 binding. Using cellular assays, we show that HIV bound to CHO cells by a CR3-dependent mechanism. Antibodies to the CR3 I-domain or to the HIV-1 envelope glycoprotein blocked the binding of HIV-1 to primary human cervical epithelial (Pex) cells, indicating that CR3 was necessary and sufficient for HIV-1 adherence to Pex cells. Using Pex cells in a Transwell model system, we show that, following transcytosis across an intact Pex cell monolayer, HIV-1 is able to infect TZM-bl reporter cells. Targeting the HIV-CR3 interaction using antibodies, mannose-binding lectins, or CR3-binding small-molecule drugs blocked HIV transcytosis. These studies indicate that CR3/Pex may constitute an efficient pathway for HIV-1 transmission in women and also demonstrate strategies that may prevent transmission via this pathway. American Society for Microbiology 2022-01-11 /pmc/articles/PMC8749410/ /pubmed/35012346 http://dx.doi.org/10.1128/mbio.02177-21 Text en Copyright © 2022 Day et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Day, Christopher J.
Hardison, Rachael L.
Spillings, Belinda L.
Poole, Jessica
Jurcisek, Joseph A.
Mak, Johnson
Jennings, Michael P.
Edwards, Jennifer L.
Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title_full Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title_fullStr Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title_full_unstemmed Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title_short Complement Receptor 3 Mediates HIV-1 Transcytosis across an Intact Cervical Epithelial Cell Barrier: New Insight into HIV Transmission in Women
title_sort complement receptor 3 mediates hiv-1 transcytosis across an intact cervical epithelial cell barrier: new insight into hiv transmission in women
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749410/
https://www.ncbi.nlm.nih.gov/pubmed/35012346
http://dx.doi.org/10.1128/mbio.02177-21
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