title: The adult penile urethra is a novel entry site for HIV-1 that preferentially targets resident urethral macrophages.
abstract: The penile urethra is routinely targeted by sexually transmitted bacterial and viral pathogens, and also represents a probable site for HIV type-1 (HIV-1) entry. Yet, the mechanisms of urethral HIV-1 transmission are unknown. To describe the initial steps of penile HIV-1 entry, we obtained whole penile tissues from individuals undergoing elective gender reassignment and developed ex vivo polarized explants of different penile epithelia, as well as in vitro immunocompetent reconstructed urethra. In penile explants, 1 h exposure to cell-associated HIV-1 results in higher HIV-1 entry into the urethra, whereas the fossa navicularis and glans are relatively resistant to HIV-1. CCR5+/CD4+ urethral macrophages are the initial cells infected by HIV-1, which exit the epithelial compartment following inoculation with cell-associated HIV-1 that induces decreased CCL2/MCP-1 production. Urethral T cells are mostly CD8+ or naive CD4+, and not infected by HIV-1 on its early entry. In urethral reconstructions, efficient translocation of cell-associated HIV-1 depends on viral tropism (R5>X4) and can be decreased by gp41-specific IgAs. Cell-free HIV-1 is inefficient at urethral penetration. Our results identify the male urethra as a novel entry site for HIV-1 that targets resident urethral macrophages. These results might explain the incomplete prophylactic efficacy of male circumcision in reducing HIV-1 transmission.
authors.affiliation: Department of Mucosal Entry of HIV-1 and Mucosal Immunity, Cell Biology, and Host Pathogen Interactions, Cochin Institute, INSERM, U1016, Paris, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Ganor
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Bodo
authors.forename: D
authors.initials: D
authors.lastname: Tudor
authors.forename: J
authors.initials: J
authors.lastname: Leibowitch
authors.forename: D
authors.initials: D
authors.lastname: Mathez
authors.forename: A
authors.initials: A
authors.lastname: Schmitt
authors.forename: M-C
authors.initials: MC
authors.lastname: Vacher-Lavenu
authors.forename: M
authors.initials: M
authors.lastname: Revol
authors.forename: M
authors.initials: M
authors.lastname: Bomsel
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015700:HIV Envelope Protein gp41 / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism; D066298:In Vitro Techniques; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D010413:Penis / Q000276:immunology / Q000821:virology; D010641:Phenotype; D021381:Protein Transport; D015728:Receptors, HIV / Q000378:metabolism; D014521:Urethra / Q000276:immunology* / Q000821:virology*; D055815:Young Adult
chemical_list: D015700:HIV Envelope Protein gp41; D007070:Immunoglobulin A; D015728:Receptors, HIV