title: Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6+ CD4+ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection.
abstract: In this study, we investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4+T cells to HIV-1 infection by focusing our experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4+T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that permit us to study the effect of TLR2 triggering on virus production at both population and single-cell levels. We report here that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6+CD4+T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are seen in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-κB p65 subunit was also detected in CD3/CD28-costimulated CCR6+CD4+T cells. We propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6+CD4+T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection.
  
  
  
  Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4+T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/CD28-costimulated CCR6+CD4+T cells leads to enhanced virus production. Our results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6+CD4+T cells to productive HIV-1 infection.
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bolduc
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Ouellet
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Hany
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Canada michel.j.tremblay@crchudequebec.ulaval.ca.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Tremblay
mesh_terms: D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D054418:Chemokine CCL20; D016328:NF-kappa B; D019713:Receptors, CCR5; D054399:Receptors, CCR6; D051195:Toll-Like Receptor 2
keywords: CD4+ T cells; NF-κB; human immunodeficiency virus