The functional role of naturally occurring antibodies against HIV-1 in human genital mucosa
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Sexual transmission of the Human Immunodeficiency Virus Type 1 (HIV-1) accounts for the majority of newly acquired infections. Vaccination efforts have induced only modest protection in HIV clinical trials. HIV-1 induces a robust local immune response in genital mucosa of exposed individuals. Understanding the function of naturally occurring antibodies against HIV-1 in genital mucosa, the primary site of transmission, might be instrumental to improving vaccines and antibody-based microbicides. This study focused on HIV-specific antibody responses in the male genital tract (MGT), which is underexplored. We characterized antibody subclasses and specificities in genital tract secretions (seminal plasma, urethral secretions) and blood from a cohort of HIV-1-infected men to determine the origin and distinct nature of antibodies in the MGT. We detected similar HIV-1 IgG titers and specificities in all three body fluids, indicating that MGT IgG likely originates from blood. In contrast, gp41-specific IgA was restricted to genital secretions suggesting a local niche of IgA antibody production. Genital secretions from a subset of individuals neutralized cell-free HIV-1 and blocked cell-to-cell HIV-1 transmission. Statistically, these functions correlated positively with gp41 IgA titers. HIV-specific IgA monoclonal antibodies were also effective in these assays. To explore cell-dependent activities of HIV-specific antibodies in genital mucosa we surveyed Fc receptor expression in mucosal epithelial tissue. The IgG-engaging neonatal Fc receptor (FcRn), the IgA receptor FcαRI and the high-affinity intracellular Fc receptor TRIM21 were detected by immunohistochemistry and western blots. In stratified squamous epithelia (foreskin, vagina) FcRn+ epithelial cells were detected primarily in the basal layer, FcαRI+ epithelial cells in suprabasal layers and TRIM21 throughout. Deposits of immunoglobulins in the stratified squamous epithelium colocalized with FcRn, FcαRI and TRIM21. Our findings indicate that the MGT is capable of expressing a local anti-HIV IgA response to achieve antiviral defense through antibody neutralization and cell-dependent functions involving classical immune effector cells and epithelial cells.
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