Antibody-dependent cellular cytotoxicity targeting CD4-inducible epitopes predicts mortality in HIV-infected infants

• Published in: EBioMedicine Vol. 47; pp. 257 - 268
• Main Authors: Naiman, Nicole E., Slyker, Jennifer, Richardson, Barbra A., John-Stewart, Grace, Nduati, Ruth, Overbaugh, Julie M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2019; Elsevier
• Subjects: ADCC; Age Factors; Antibody-Dependent Cell Cytotoxicity - immunology; CD4 Antigens - immunology; CD4-inducible epitopes; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Epitopes - immunology; HIV; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV Infections - mortality; HIV Infections - transmission; HIV Infections - virology; HIV-1 - immunology; Humans; Infant; Mother-to-child transmission; Prognosis; Research paper; HIV; CD4-inducible epitopes; ADCC; Mother-to-child transmission
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.08.072

Antibody-dependent cellular cytotoxicity (ADCC) has been associated with improved infant outcome in mother-to-child transmission (MTCT) of HIV-1. Epitopes of these ADCC-mediating antibodies remain unidentified. CD4-inducible (CD4i) epitopes on gp120 are common ADCC targets in natural infection and vaccination. We tested whether CD4i epitope-specific ADCC mediated by maternal antibodies or passively-acquired antibodies in infants is associated with reduced MTCT and improved infant survival. We used variants of CD4i cluster A-specific antibodies, A32 and C11, and a cluster C-specific antibody, 17b, with mutations abolishing Fc–Fc receptor interactions as inhibitors in a competition rapid and fluorometric ADCC assay using gp120-coated CEM-nkr target cells with plasma from 51 non-transmitting and 21 transmitting breastfeeding mother-infant pairs. Cluster A-specific ADCC was common. Individually, neither A32-like nor C11-like ADCC was statistically significantly associated with risk of MTCT or infected infant survival. In combination, total maternal cluster A-specific ADCC was statistically significantly associated with decreased infected infant survival in a log-rank test (p = 0·017). There was a non-significant association for infant passively-acquired total cluster A-specific ADCC and decreased infected infant survival (p = 0·14). Surprisingly, plasma ADCC was enhanced in the presence of the defective Fc 17b competitor. Defective Fc 17b competitor-mediated maternal ADCC enhancement was statistically significantly associated with reduced infected infant survival (p = 0·011). A non-significant association was observed for passively-acquired infant ADCC enhancement and decreased survival (p = 0·19). These data suggest that ADCC targeting CD4i epitopes is not associated with protection against breast milk HIV transmission but is associated with decreased survival of infected infants. This study was funded by NIH grant R01AI076105 and NIH fellowship F30AI136636.