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bioRxiv · 10.1101/2021.10.14.464395

Impact of IgG isotype on the induction of antibody-dependent cellular phagocytosis of HIV by human milk leukocytes

Fox, A.·Liu, X.·Zolla-Pazner, S.·Powell, R. L.
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Abstract

Approximately 100,000 mother-to-child transmission (MTCT) events of HIV via human milk feeding occur each year (1). However, only about 15% of infants milk-fed by untreated HIV+ mothers become infected, suggesting a protective effect of the milk itself (1, 2). Infants ingest 105-108 maternal leukocytes daily via milk, which remain functional beyond ingestion (3-9). Such function may be elicited by maternal milk antibody (Ab). Though IgA is dominant in milk, most HIV-specific milk Abs are of the IgG subclass, highlighting the importance of investigating the function of each IgG isotype in the milk context (10-16). Though Ab effector function mediated by the constant (Fc) domain via interaction with Fc Receptors (FcRs), such as Ab-dependent cellular phagocytosis (ADCP), are critical in protecting against HIV infection, ADCP is largely unexplored as it relates to mitigation of MTCT (17-21). Presently we report the ADCP activity of milk leukocytes against HIV particles and immune complexes (ICs), using 57 unique samples from 34 women, elicited by IgG1/2/3/4 of monoclonal (m)Ab 246-D. Granulocyte ADCP of HIV was most potent compared to other phagocytes when elicited by IgG1/3/4. IgG1/3 activated granulocytes similarly, exhibiting 1.6x-4.4x greater activity compared to IgG2/4, and a preference for virus compared to ICs. Notably, CD16-monocyte ADCP of a given target were unaffected by isotype, and CD16+ monocytes were poorly stimulated by IgG1. IgG2/4 elicited potent IC ADCP, and in terms of total leukocyte IC ADCP, IgG4 and IgG3 exhibited similar function, with IgG4 eliciting 1.6x-2.1x greater activity compared to IgG1/IgG2, and CD16+ monocytes most stimulated by IgG2. These data contribute to a more comprehensive understanding of Fc-mediated functionality of milk leukocytes, which is critical in order to develop therapeutic approaches to eliminating this route of MTCT, including mucosal administration of mAbs and/or a maternal vaccination aimed to elicit a potent milk Ab response.

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Fox, A., Liu, X., Zolla-Pazner, S., Powell, R. L.. 2021-10-15. Impact of IgG isotype on the induction of antibody-dependent cellular phagocytosis of HIV by human milk leukocytes. https://doi.org/10.1101/2021.10.14.464395

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