Dendritic Cells From the Cervical Mucosa Capture and Transfer HIV-1 via Siglec-1

Antigen presenting cells from the cervical mucosa are thought to amplify incoming HIV-1 and spread infection systemically without being productively infected. Yet, the molecular mechanism at the cervical mucosa underlying this viral transmission pathway remains unknown. Here we identified a subset of HLA-DR+ CD14+ CD11c+ cervical DCs at the lamina propria of the ectocervix and the endocervix that expressed the type-I interferon inducible lectin Siglec-1 (CD169), which promoted viral uptake. In the cervical biopsy of a viremic HIV-1+ patient, Siglec-1+ cells harbored HIV-1-containing compartments, demonstrating that in vivo, these cells trap viruses. Ex vivo, a type-I interferon antiviral environment enhanced viral capture and trans-infection via Siglec-1. Nonetheless, HIV-1 transfer via cervical DCs was effectively prevented with antibodies against Siglec-1. Our findings contribute to decipher how cervical DCs may boost HIV-1 replication and promote systemic viral spread from the cervical mucosa, and highlight the importance of including inhibitors against Siglec-1 in microbicidal strategies.

[1]  J. Lieberman,et al.  Myeloid Cells in Intact Human Cervical Explants Capture HIV and Can Transmit It to CD4 T Cells , 2018, Front. Immunol..

[2]  M. Genescà,et al.  Maximizing the immunological output of the cervicovaginal explant model. , 2018, Journal of immunological methods.

[3]  Y. Koyanagi,et al.  Type I Interferon Responses by HIV-1 Infection: Association with Disease Progression and Control , 2018, Front. Immunol..

[4]  G. Learn,et al.  Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness , 2017, Proceedings of the National Academy of Sciences.

[5]  J. Kappes,et al.  Dendritic Cells from the Human Female Reproductive Tract Rapidly Capture and respond to HIV , 2016, Mucosal Immunology.

[6]  T. Hope,et al.  Th17 Cells Are Preferentially Infected Very Early after Vaginal Transmission of SIV in Macaques. , 2016, Cell host & microbe.

[7]  P. Uchil,et al.  Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection , 2015, Science.

[8]  P. Hertzog,et al.  Blocking HIV-1 transmission in the female reproductive tract: from microbicide development to exploring local antiviral responses , 2015, Clinical & translational immunology.

[9]  A. Telenti,et al.  HIV-1 immune activation induces Siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells , 2015, Retrovirology.

[10]  M. Malim,et al.  HIV-1 and interferons: who's interfering with whom? , 2015, Nature Reviews Microbiology.

[11]  T. Hope,et al.  Vaginal Challenge with an SIV-Based Dual Reporter System Reveals That Infection Can Occur throughout the Upper and Lower Female Reproductive Tract , 2014, PLoS pathogens.

[12]  J. Kappes,et al.  Vaginal Myeloid Dendritic Cells Transmit Founder HIV-1 , 2014, Journal of Virology.

[13]  J. Lieberman,et al.  Distribution of Immune Cells in the Human Cervix and Implications for HIV Transmission , 2014, American journal of reproductive immunology.

[14]  M. Altfeld,et al.  Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication. , 2013, The Journal of infectious diseases.

[15]  B. Reinhard,et al.  Interferon-Inducible Mechanism of Dendritic Cell-Mediated HIV-1 Dissemination Is Dependent on Siglec-1/CD169 , 2013, PLoS pathogens.

[16]  V. Soumelis,et al.  Human inflammatory dendritic cells induce Th17 cell differentiation. , 2013, Immunity.

[17]  J. Banchereau,et al.  Functional diversity of human vaginal APC subsets in directing T cell responses , 2012, Mucosal Immunology.

[18]  A. Telenti,et al.  Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides , 2012, PLoS biology.

[19]  B. Reinhard,et al.  HIV-1 incorporation of host-cell–derived glycosphingolipid GM3 allows for capture by mature dendritic cells , 2012, Proceedings of the National Academy of Sciences.

[20]  J. Martinez-Picado,et al.  Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1 , 2012, PLoS biology.

[21]  M. McElrath,et al.  Vaginal Langerhans Cells Nonproductively Transporting HIV-1 Mediate Infection of T Cells , 2011, Journal of Virology.

[22]  J. Fahey,et al.  Innate and adaptive immunity at mucosal surfaces of the female reproductive tract: stratification and integration of immune protection against the transmission of sexually transmitted infections. , 2011, Journal of reproductive immunology.

[23]  A. Iwasaki.  Antiviral immune responses in the genital tract: clues for vaccines , 2010, Nature Reviews Immunology.

[24]  Ashley T. Haase,et al.  Targeting early infection to prevent HIV-1 mucosal transmission , 2010, Nature.

[25]  M. Altfeld,et al.  Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1 , 2009, Nature Medicine.

[26]  S. Pambuccian,et al.  Glycerol monolaurate prevents mucosal SIV transmission , 2009, Nature.

[27]  P. Wallace,et al.  Recruitment of myeloid and plasmacytoid dendritic cells in cervical mucosa during Chlamydia trachomatis infection. , 2009, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[28]  Morgan A Reuter,et al.  HIV Traffics through a Specialized, Surface-Accessible Intracellular Compartment during trans-Infection of T Cells by Mature Dendritic Cells , 2008, PLoS pathogens.

[29]  L. Pulliam,et al.  Sialoadhesin Expressed on IFN-Induced Monocytes Binds HIV-1 and Enhances Infectivity , 2008, PloS one.

[30]  Li Wu,et al.  Functionally Distinct Transmission of Human Immunodeficiency Virus Type 1 Mediated by Immature and Mature Dendritic Cells , 2007, Journal of Virology.

[31]  B. Clotet,et al.  Maturation of Blood-Derived Dendritic Cells Enhances Human Immunodeficiency Virus Type 1 Capture and Transmission , 2007, Journal of Virology.

[32]  A. Iwasaki.  Mucosal dendritic cells. , 2007, Annual review of immunology.

[33]  D. Littman,et al.  Dendritic Cell-Mediated trans-Enhancement of Human Immunodeficiency Virus Type 1 Infectivity Is Independent of DC-SIGN , 2006, Journal of Virology.

[34]  A. Iwasaki,et al.  Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ1 , 2006, The Journal of Immunology.

[35]  M. Lederman,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Nature Medicine.

[36]  L. Lopalco,et al.  Upregulation of Interferon-α and RANTES in the Cervix of HIV-1-Seronegative Women With High-Risk Behavior , 2006, Journal of acquired immune deficiency syndromes.

[37]  Arthur M. Krieg,et al.  The Toll-Like Receptor 7 (TLR7) Agonist, Imiquimod, and the TLR9 Agonist, CpG ODN, Induce Antiviral Cytokines and Chemokines but Do Not Prevent Vaginal Transmission of Simian Immunodeficiency Virus When Applied Intravaginally to Rhesus Macaques , 2005, Journal of Virology.

[38]  J. Lifson,et al.  Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. , 2005, The Journal of clinical investigation.

[39]  R. Steinman,et al.  Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin/CD209 Is Abundant on Macrophages in the Normal Human Lymph Node and Is Not Required for Dendritic Cell Stimulation of the Mixed Leukocyte Reaction1 , 2005, The Journal of Immunology.

[40]  David M. Rocke,et al.  Temporal and Anatomic Relationship between Virus Replication and Cytokine Gene Expression after Vaginal Simian Immunodeficiency Virus Infection , 2005, Journal of Virology.

[41]  Eun-Young Kim,et al.  Propagation and Dissemination of Infection after Vaginal Transmission of Simian Immunodeficiency Virus , 2005, Journal of Virology.

[42]  J. Barretina,et al.  R5 HIV gp120‐mediated cellular contacts induce the death of single CCR5‐expressing CD4 T cells by a gp41‐dependent mechanism , 2004, Journal of leukocyte biology.

[43]  John P. Moore,et al.  Blockade of Attachment and Fusion Receptors Inhibits HIV-1 Infection of Human Cervical Tissue , 2004, The Journal of experimental medicine.

[44]  J. Lifson,et al.  Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. , 2004, Blood.

[45]  L. Stamatatos,et al.  Binding of Human Immunodeficiency Virus Type 1 to Immature Dendritic Cells Can Occur Independently of DC-SIGN and Mannose Binding C-Type Lectin Receptors via a Cholesterol-Dependent Pathway , 2003, Journal of Virology.

[46]  John P. Moore,et al.  Inhibiting sexual transmission of HIV-1 infection , 2003, Nature Reviews Microbiology.

[47]  D. McDonald,et al.  Recruitment of HIV and Its Receptors to Dendritic Cell-T Cell Junctions , 2003, Science.

[48]  Takashi Uchiyama,et al.  Natural Alpha Interferon-Producing Cells Respond to Human Immunodeficiency Virus Type 1 with Alpha Interferon Production and Maturation into Dendritic Cells , 2003, Journal of Virology.

[49]  R. Steinman,et al.  Cell type-dependent retention and transmission of HIV-1 by DC-SIGN. , 2003, International immunology.

[50]  R. Doms,et al.  Diversity of receptors binding HIV on dendritic cell subsets , 2002, Nature Immunology.

[51]  B. Berkhout,et al.  Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells , 2002, Journal of Virology.

[52]  V. KewalRamani,et al.  Rhesus macaque dendritic cells efficiently transmit primate lentiviruses independently of DC-SIGN , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Christopher J. Miller,et al.  Simian Immunodeficiency Virus Rapidly Penetrates the Cervicovaginal Mucosa after Intravaginal Inoculation and Infects Intraepithelial Dendritic Cells , 2000, Journal of Virology.

[54]  Douglas S Kwon,et al.  DC-SIGN, a Dendritic Cell–Specific HIV-1-Binding Protein that Enhances trans-Infection of T Cells , 2000, Cell.

[55]  D. Klatzmann,et al.  Dendritic Cells Route Human Immunodeficiency Virus to Lymph Nodes after Vaginal or Intravenous Administration to Mice , 1998, Journal of Virology.

[56]  A I Spira,et al.  Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques , 1996, The Journal of experimental medicine.

[57]  R. Steinman,et al.  Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1 , 1994, Cell.

[58]  K Inaba,et al.  Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. , 1992, Science.