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Antibody-based protection against HIV infection by vectored immunoprophylaxis


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.


  1. Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010)

    Article  ADS  CAS  Google Scholar 

  2. Walker, L. M. et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009)

    Article  ADS  CAS  Google Scholar 

  3. Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011)

    Article  ADS  CAS  Google Scholar 

  4. Wu, X. et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333, 1593–1602 (2011)

    Article  ADS  CAS  Google Scholar 

  5. Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011)

    Article  ADS  CAS  Google Scholar 

  6. Zhou, T. et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010)

    Article  ADS  CAS  Google Scholar 

  7. Scheid, J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636–640 (2009)

    Article  ADS  CAS  Google Scholar 

  8. Kwong, P. D. & Wilson, I. A. HIV-1 and influenza antibodies: seeing antigens in new ways. Nature Immunol. 10, 573–578 (2009)

    Article  CAS  Google Scholar 

  9. Burton, D. R. et al. HIV vaccine design and the neutralizing antibody problem. Nature Immunol. 5, 233–236 (2004)

    Article  CAS  Google Scholar 

  10. Dormitzer, P. R., Ulmer, J. B. & Rappuoli, R. Structure-based antigen design: a strategy for next generation vaccines. Trends Biotechnol. 26, 659–667 (2008)

    Article  CAS  Google Scholar 

  11. Lewis, A. D., Chen, R., Montefiori, D. C., Johnson, P. R. & Clark, K. R. Generation of neutralizing activity against human immunodeficiency virus type 1 in serum by antibody gene transfer. J. Virol. 76, 8769–8775 (2002)

    Article  CAS  Google Scholar 

  12. Fang, J. et al. Stable antibody expression at therapeutic levels using the 2A peptide. Nature Biotechnol. 23, 584–590 (2005)

    Article  CAS  Google Scholar 

  13. McCarty, D. M. Self-complementary AAV vectors; advances and applications. Mol. Ther. 16, 1648–1656 (2008)

    Article  MathSciNet  CAS  Google Scholar 

  14. Johnson, P. R. et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nature Med. 15, 901–906 (2009)

    Article  CAS  Google Scholar 

  15. Gao, G. P. et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 99, 11854–11859 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Breous, E., Somanathan, S. & Wilson, J. M. BALB/c mice show impaired hepatic tolerogenic response following AAV gene transfer to the liver. Mol. Ther. 18, 766–774 (2010)

    Article  CAS  Google Scholar 

  17. Kumar, P. et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134, 577–586 (2008)

    Article  CAS  Google Scholar 

  18. Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005)

    Article  ADS  CAS  Google Scholar 

  19. Binley, J. M. et al. Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies. J. Virol. 78, 13232–13252 (2004)

    Article  CAS  Google Scholar 

  20. Wawer, M. J. et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J. Infect. Dis. 191, 1403–1409 (2005)

    Article  Google Scholar 

  21. Salazar-Gonzalez, J. F. et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J. Virol. 82, 3952–3970 (2008)

    Article  CAS  Google Scholar 

  22. Fang, J. et al. An antibody delivery system for regulated expression of therapeutic levels of monoclonal antibodies in vivo . Mol. Ther. 15, 1153–1159 (2007)

    Article  CAS  Google Scholar 

  23. West, A. P., Jr, Galimidi, R. P., Gnanapragasam, P. N. P. & Bjorkman, P. J. Single chain Fv-based anti-HIV proteins: potential and limitations. J. Virol. 10.1128/JVI.05848-11 (19 October 2011)

  24. Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008)

    Article  CAS  Google Scholar 

  25. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature Med. 12, 342–347 (2006)

    Article  CAS  Google Scholar 

  26. Vandenberghe, L. H. et al. Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nature Med. 12, 967–971 (2006)

    Article  CAS  Google Scholar 

  27. Jiang, H. et al. Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol. Ther. 14, 452–455 (2006)

    Article  CAS  Google Scholar 

  28. Morell, A., Terry, W. D. & Waldmann, T. A. Metabolic properties of IgG subclasses in man. J. Clin. Invest. 49, 673–680 (1970)

    Article  CAS  Google Scholar 

  29. Petkova, S. B. et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int. Immunol. 18, 1759–1769 (2006)

    Article  CAS  Google Scholar 

  30. Diskin, R. et al. Increasing the potency and breadth of an HIV antibody using structure-based rational design. Science 10.1126/science.1213782 (27 October 2011)

  31. Lock, M. et al. Rapid, simple, and versatile manufacturing of recombinant adeno-associated viral vectors at scale. Hum. Gene Ther. 21, 1259–1271 (2010)

    Article  CAS  Google Scholar 

  32. Ayuso, E. et al. High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency. Gene Ther. 17, 503–510 (2010)

    Article  CAS  Google Scholar 

  33. Matsushita, T. et al. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 5, 938–945 (1998)

    Article  CAS  Google Scholar 

  34. Wright, J. F. et al. Identification of factors that contribute to recombinant AAV2 particle aggregation and methods to prevent its occurrence during vector purification and formulation. Mol. Ther. 12, 171–178 (2005)

    Article  CAS  Google Scholar 

  35. Rohr, U. P. et al. Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. J. Virol. Methods 106, 81–88 (2002)

    Article  CAS  Google Scholar 

  36. Adachi, A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Montefiori, D. C. Evaluating neutralizing antibodies against HIV, SIV, and SHIV in luciferase reporter gene assays. Curr. Protocol. Immunol. Ch. 12.11,. 10.1002/0471142735.im1211s64 (2005)

  38. Kaluza, G. et al. A monoclonal antibody that recognizes a formalin-resistant epitope on the p 24 core protein of HIV-1. Pathol. Res. Pract. 188, 91–96 (1992)

    Article  CAS  Google Scholar 

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

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