Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys

Abstract

Breast milk HIV-1 transmission is currently the predominant contributor to pediatric HIV infections. Yet, only ~10% of breastfeeding infants born to untreated HIV-infected mothers become infected. This study assessed the protective capacity of natural HIV envelope-specific antibodies isolated from the milk of HIV-infected women in an infant rhesus monkey (RM), tier 2 SHIV oral challenge model. To mimic placental and milk maternal antibody transfer, infant RMs were i.v. infused and orally treated at the time of challenge with a single weakly neutralizing milk monoclonal antibody (mAb), a tri-mAb cocktail with weakly neutralizing and ADCC functionalities, or an anti-influenza control mAb. Of these groups, the fewest tri-mAb-treated infants had SHIV detectable in plasma or tissues (2/6, 5/6, and 7/8 animals infected in tri-mAb, single-mAb, and control-mAb groups, respectively). Tri-mAb-treated infants demonstrated significantly fewer plasma transmitted/founder variants and reduced peripheral CD4+ T cell proviral loads at 8 weeks post-challenge compared to control mAb-treated infants. Abortive infection was observed as detectable CD4+ T cell provirus in non-viremic control mAb- and single mAb-, but not in tri-mAb-treated animals. These results suggest that polyfunctional milk antibodies contribute to the natural inefficiency of HIV-1 transmission through breastfeeding and infant vaccinations eliciting non-neutralizing antibody responses could reduce postnatal HIV transmission.

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Acknowledgements

We thank Ruth Ruprect and the Dana Farber Cancer Institute for generously permitting the use of the SHIV-1157ipd3N4 for challenging the animals in this study through the NIH AIDS reagent Program. We also thank the Duke Human Vaccine Institute Protein Production Facility for help with mAb production, the Duke University Sequencing and Genomic Technology core facility for help with the ddPCR and Fluidigm assays, Barton Haynes and Kevin Saunders for providing protein antigens used in ELISAs, Tori Huffman and R. Whitney Edwards for technical assistance on ADCC data collection, David O’Connor and Roger Wiseman at the Wisconson National Primate Center for performing the MHC-typing, and the NIH HIV Research and Design (HIVRAD) and Research Project Grant (R01) programs for funding. TZM-bl cells and SG3Δenv were provided by John Kappes and Xiaoyun Wu through the NIH AIDS Reagent Program. This work was funded by HHS/National Institutes of Health (R01AI1063980, P01AI117915).

Author information

S.P., J.E.H., J.P., R.G., and R.J.M. contributed to study design. J.E.H., R.G., R.J.M., A.K., T.L.J., Q.N.N., J.W.P., G.F., C.L., D.C.M., C.M., X.A.-H., F.S., and P.P.A. contributed to immunologic and virologic assays and data collection. J.E.H., R.G., R.J.M., J.A.E., H.H., F.S., and P.P.A. contributed to tissue processing and sample collection. J.W.P. produced study antibodies. J.E.H., R.G., R.J.M., S.P., F.S., and P.P.A. contributed to animal management. J.E.H., R.G., R.J.M., A.K., J.W.P., and S.R.P. drafted the manuscript. M.C. and N.A.V. performed power calculations and statistical analyses.

Correspondence to Sallie R. Permar.

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