Antibody-based protection against HIV infection by vectored immunoprophylaxis

Abstract

Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains1,2,3,4,5. These antibodies all exhibit an unusually high level of somatic mutation6, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen7. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes8,9,10, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.

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Figure 1: VIP protects against HIV-mediated CD4 cell depletion in humanized mice.
Figure 2: Comparison of protection mediated by various broadly neutralizing HIV antibodies.
Figure 3: Robustness of CD4 cell protection mediated by b12 antibody.
Figure 4: Determination of the minimum protective dose of VRC01 in vivo.

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Acknowledgements

We thank J. Wilson for AAV8-related plasmids and assistance, D. Burton for b12 and 2G12 expression plasmids, G. Nabel for 4E10, 2F5 and VRC01 expression plasmids, and the Caltech Protein Expression Center for providing purified antibodies. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: pNL4-3 from M. Martin, and TZM-bl cells from J. Kappes and X. Wu. We thank J. Bloom, D. Kotton, D. Majumdar, G. Mostoslavsky, R. O’Connell and A. Sigal for comments, and other members of the Baltimore laboratory for their assistance in performing this work. This project was supported by the Bill and Melinda Gates Foundation through Grand Challenges in Global Health Initiative (awarded to D.B.) Grand Challenge grant 37866 and by the National Institutes of Health (HHSN266200500035C) through a contract from the National Institute of Allergy and Infectious Disease (NIAID) and by the Joint Center for Translational Medicine. A.B.B. is supported by amfAR postdoctoral research fellowship 107756-47-RFVA. D.S.R. is supported by career development award 1K08CA133521 from the National Institutes of Health.

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A.B.B. and D.B. conceived the study with assistance from L.Y. A.B.B. designed the experiments. A.B.B., J.C. and C.M.H. performed experiments. A.B.B., J.C. and C.M.H. analysed the data. D.S.R. performed immunohistochemistry and analysis. A.B.B. and D.B. wrote the paper with contributions from all authors.

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Correspondence to David Baltimore.

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The authors declare no competing financial interests.

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Balazs, A., Chen, J., Hong, C. et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481, 81–84 (2012). https://doi.org/10.1038/nature10660

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