ABSTRACT
Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.
Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , B-Lymphocytes/immunology , Colostrum/immunology , HIV Antibodies/chemistry , HIV Envelope Protein gp120/antagonists & inhibitors , Immunoglobulin G/chemistry , Antibodies, Monoclonal/biosynthesis , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/isolation & purification , Antibody Affinity , Antibody Specificity , B-Lymphocytes/pathology , B-Lymphocytes/virology , Breast Feeding , Colostrum/cytology , Colostrum/virology , Cross Reactions , Dendritic Cells/immunology , Dendritic Cells/pathology , Dendritic Cells/virology , Disease Resistance/immunology , Epithelial Cells/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Gastrointestinal Microbiome/immunology , HIV Antibodies/biosynthesis , HIV Antibodies/isolation & purification , HIV Envelope Protein gp120/immunology , HIV Infections/immunology , HIV Infections/pathology , HIV Infections/virology , HIV-1/immunology , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin G/isolation & purification , Infant , Infectious Disease Transmission, Vertical/prevention & control , Milk, Human/chemistry , Milk, Human/immunology , Milk, Human/virology , Pregnancy , Symbiosis/immunologyABSTRACT
A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(â¼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.
