TY - JOUR
T1 - Natural mucosal antibodies reactive with first extracellular loop of CCR5 inhibit HIV-1 transport across human epithelial cells
AU - Bomsel, Morgane
AU - Pastori, Claudia
AU - Tudor, Daniela
AU - Alberti, Chiara
AU - Garcia, Severine
AU - Ferrari, Davide
AU - Lazzarin, Adriano
AU - Lopalco, Lucia
PY - 2007/1
Y1 - 2007/1
N2 - OBJECTIVE: 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. DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
AB - OBJECTIVE: 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. DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
KW - Anti-CCR5 antibodies
KW - CCR5
KW - HIV
KW - Mucosal IgA
KW - Neutralizing antibodies
KW - Transcytosis
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U2 - 10.1097/QAD.0b013e328011049b
DO - 10.1097/QAD.0b013e328011049b
M3 - Article
C2 - 17148963
AN - SCOPUS:33845496088
VL - 21
SP - 13
EP - 22
JO - AIDS
JF - AIDS
SN - 0269-9370
IS - 1
ER -