Two sides to the same antibody: assessing the role of neutralizing and non-neutralizing antibodies in mother-to-child transmission of HIV-1
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Passive immunization with neutralizing antibodies (nAbs) may prevent mother-to-child transmission (MTCT) of HIV-1 and/or impact HIV-1 exposed infant outcomes. This study compared plasma neutralizing activity against heterologous HIV-1 variants and the quasispecies present in the infected mothers among exposed uninfected infants (HEU) to infants that eventually acquired infection and between transmitting versus non-transmitting mothers. HEU (n = 42), compared to those that eventually acquired infection (n = 21), did not possess higher nAb responses against heterologous envelopes (p = 0.46) or their mothers’ variants (p = 0.45). Transmitting as compared to non-transmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (p = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (p = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (p = 0.03). These results imply that pre-existing anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both frequency of breast milk transmission and subsequent infant morbidity. In addition to neutralization, passively acquired maternal antibodies that mediate antibody dependent cellular cytotoxicity (ADCC) may impact both breast milk transmission and infant outcomes. To date, no study has rigorously compared ADCC activity against a broad panel of heterologous strains or circulating maternal viruses among HEU versus infants that eventually acquire infection and among transmitting versus non-transmitting mothers. We developed a high-throughput assay that measures the lysis of infected reporter target cells in the presence and absence of antibodies. This assay yields similar results as other methods that use decreases in reporter signal from target cells or lysis of primary cells estimated by flow cytometry. In contrast to other ADCC methods, we show that our assay allows assessment of ADCC breadth and potency in a relatively high throughput manner because it uses novel target cells that are susceptible to infection by diverse HIV-1 variants. Estimating ADCC breadth and potency and activity against maternal strains will have important insights about the impact of passively acquired maternal antibodies on MTCT.