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The genital mucosa represents the major site for initial host-HIV-1 contact. HIV-1-protective mucosal immunity has been identified either in subjects who despite repeated sexual exposure, remain seronegative (ESN) or in long-term non-progressor HIV-1-seropositive individuals (LTNP). As a subset of ESN and LTNP produce anti-CCR5 antibodies both at systemic and mucosal level, we studied the role of anti-CCR5 antibodies in blocking HIV transfer through human epithelial cells.To evaluate HIV-1-inhibitory activity by anti-CCR5 antibodies, a two-chambers system was established to model HIV-1 infection across the human mucosal epithelium. Moreover, peripheral blood mononuclear cells (PBMC) and a CCR5 transfected cell line were also used in a classical HIV-infectivity assay. CCR5-specific IgG and IgA were used to inhibit HIV replication.Either serum or mucosal IgA to CCR5 were able to specifically block transcytosis of CCR5- but not CXCR4-HIV strains across a tight epithelial cell layer by interacting with the first extracellular loop of the receptor (amino acids YAAAQWDFGNTMCQ). Monoclonal antibodies against other regions of CCR5 had no effect on HIV transcytosis. Moreover, mucosal CCR5-specific IgA neutralized CCR5-tropic strains and SOS–JRFL pseudovirus replication in PBMC and CCR5 transfected cell lines respectively, with a mechanism different than that observed for transcytosis.Anti-CCR5 Abs shed light on the immunological mechanisms involved in the control of HIV-1 infection in a model that can be considered an experimentum naturae for resistance to HIV. They could be useful in the design of new strategies against HIV infection at mucosal sites.