title: Retinoic acid imprints a mucosal-like phenotype on dendritic cells with an increased ability to fuel HIV-1 infection.
abstract: The tissue microenvironment shapes the characteristics and functions of dendritic cells (DCs), which are important players in HIV infection and dissemination. Notably, DCs in the gut have the daunting task of orchestrating the balance between immune response and tolerance. They produce retinoic acid (RA), which imprints a gut-homing phenotype and influences surrounding DCs. To investigate how the gut microenvironment impacts the ability of DCs to drive HIV infection, we conditioned human immature monocyte-derived DCs (moDCs) with RA (RA-DCs), before pulsing them with HIV and mixing them with autologous T cells. RA-DCs showed a semimature, mucosal-like phenotype and released higher amounts of TGF-β1 and CCL2. Using flow cytometry, Western blot, and microscopy, we determined that moDCs express the cell adhesion molecule mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and that RA increases its expression. MAdCAM-1 was also detected on a small population of DCs in rhesus macaque (Macaca mulata) mesenteric lymph node. RA-DCs formed more DC-T cell conjugates and promoted significantly higher HIV replication in DC-T cell mixtures compared with moDCs. This correlated with the increase in MAdCAM-1 expression. Blocking MAdCAM-1 partially inhibited the enhanced HIV replication. In summary, RA influences DC phenotype, increasing their ability to exacerbate HIV infection. We describe a previously unknown mechanism that may contribute to rapid HIV spread in the gut, a major site of HIV replication after mucosal exposure.
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Natalia
authors.initials: N
authors.lastname: Guerra-Pérez
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Ines
authors.initials: I
authors.lastname: Frank
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Filippo
authors.initials: F
authors.lastname: Veglia
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Meropi
authors.initials: M
authors.lastname: Aravantinou
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Diana
authors.initials: D
authors.lastname: Goode
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, LA 70433; and.
authors.forename: James L
authors.initials: JL
authors.lastname: Blanchard
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065;
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065; emartinelli@popcouncil.org.
authors.forename: Elena
authors.initials: E
authors.lastname: Martinelli
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D009088:Mucoproteins / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000378:metabolism; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D014212:Tretinoin