Impact of IgG Isotype on the Induction of Antibody-Dependent Cellular Phagocytosis of HIV by Human Milk Leukocytes

Abstract

Approximately 100,000 mother-to-child transmission (MTCT) events of HIV via human milk feeding occur each year. However, only about 15% of infants milk-fed by untreated HIV+ mothers become infected, suggesting a protective effect of the milk itself. Infants ingest 105-108 maternal leukocytes daily via milk, which remain functional beyond ingestion. 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. 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. 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.

Preventing breast milk HIV transmission using broadly neutralizing monoclonal antibodies: One size does not fit all

“…12 The chosen bNAbs would need to be safe and have a favorable PK/PD profile in neonates and infants 4 and have preferential effector functions against free viral particles and cell-associated viruses (including antibodydependent complement cytotoxicity and/or enhancement of phagocytosis). 24,25 It is therefore likely that administration to all newborns and breastfed infants of a single or dual bNAb regimen (preferentially targeting different Env epitopes) with 98% breadth against clade C (the virus circulating in southern Africa), such as VRC07-523LS and CAP256V2LS, may tentatively be highly effective in protecting against HIV transmission through breastfeeding in communities with high HIV incidence. This strategy, which complements current PMTCT initiated during pregnancy (with maternal antiretroviral therapy and PNP), has a high chance of being a game changer in the elimination of pediatric HIV.…”