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Early development of broadly neutralizing antibodies in HIV-1–infected infants

Abstract

Eliciting protective neutralizing antibodies (NAbs) against HIV-1 is daunting because of the extensive genetic and antigenic diversity of HIV-1. Moreover, broad and potent responses are uncommon even during persistent infection, with only a subset of adults developing broadly neutralizing antibodies (bNAbs) that recognize viral variants from different HIV-1 clades1,2,3,4,5,6,7,8. It is not known whether bNAbs can also arise in HIV-1–infected infants, who typically progress to disease faster than adults9, presumably in part due to an immature immune system10. Here, we show that bNAbs develop at least as commonly in infants as in adults. Cross-clade NAb responses were detected in 20/28 infected infants, in some cases within 1 year of infection. Among infants with breadth of responses within the top quartile, neutralization of tier 2 or 3 variants from multiple clades was detected at 20 months after infection. These findings suggest that, even in early life, there is sufficient B cell functionality to mount bNAbs against HIV-1. Additionally, the relatively early appearance of bNAbs in infants may provide a unique setting for understanding the pathways of B cell maturation leading to bNAbs.

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Figure 1: Neutralization of panel viruses.
Figure 2: Kinetics of NAb breadth for seven infants.
Figure 3: Association between passive and de novo NAbs.
Figure 4: Comparison of set-point viral load and Env-specific IgG for infants with and without bNAbs.

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Acknowledgements

We are grateful to the participants and staff of the Nairobi Breastfeeding Trial; P. Poignard (International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute) for providing envelope plasmids used for viruses in Supplementary Figure 2; P. Moore (Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa) and G. Shaw (Perelman School of Medicine, University of Pennsylvania) for providing 7312-A and 7312-C1 plasmids; X. Wu and J. Mascola (Vaccine Research Center, US National Institutes of Health) for providing RSC3 and RSC3d371I plasmids; N. Doria-Rose, S. O'Dell and J. Mascola (Vaccine Research Center, US National Institutes of Health) for providing JRCSF N160K and N332A plasmids; S. Rainwater and B. Wang for assistance in obtaining viral clade information; V. Cortez for assistance in RSC3 protein purification; C. Milligan for sample database management; G. John-Stewart, I. Georgiev, V. Cortez, D. Lehman, C. Milligan and K. Ronen for helpful discussions; and B. Richardson for advice on statistical analyses. This work was supported by US National Institutes of Health grants AI076105 and AI103981.

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L.G. designed and performed experiments, analyzed data and wrote the manuscript. V.C. performed experiments. R.N. oversaw the cohort and clinical aspects. J.O. conceived of and oversaw the study and edited the manuscript.

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Correspondence to Julie Overbaugh.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4 and Supplementary Tables 1 and 2 (PDF 1003 kb)

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Goo, L., Chohan, V., Nduati, R. et al. Early development of broadly neutralizing antibodies in HIV-1–infected infants. Nat Med 20, 655–658 (2014). https://doi.org/10.1038/nm.3565

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