HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

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Abstract

Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection1,2. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time3,4. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design5,6,7,8,9. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy10,11,12, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.

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Figure 1: Monotherapy using broadly neutralizing antibodies in HIV-1 YU2 -infected humanized mice.
Figure 2: HIV therapy by a combination of three (tri-mix) or five (penta-mix) broadly neutralizing antibodies in HIV-1 YU2 -infected humanized mice.
Figure 3: Viral rebound in HIV-1 YU2 -infected humanized mice after cessation of antibody therapy.

References

  1. 1

    Hessell, A. J. et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nature Med. 15, 951–954 (2009)

  2. 2

    Mascola, J. R. et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol. 73, 4009–4018 (1999)

  3. 3

    Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003)

  4. 4

    Poignard, P. et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438 (1999)

  5. 5

    Diskin, R. et al. Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334, 1289–1293 (2011)

  6. 6

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

  7. 7

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

  8. 8

    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)

  9. 9

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

  10. 10

    Choudhary, S. K. et al. Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4+ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2−/−γc−/− mouse. J. Virol. 83, 8254–8258 (2009)

  11. 11

    Nischang, M. et al. Humanized mice recapitulate key features of HIV-1 infection: A novel concept using long-acting anti-retroviral drugs for treating HIV-1. PLoS ONE 7, e38853 (2012)

  12. 12

    Denton, P. W. et al. Generation of HIV latency in humanized BLT mice. J. Virol. 86, 630–634 (2012)

  13. 13

    Weiss, R. A. Special anniversary review: twenty-five years of human immunodeficiency virus research: successes and challenges. Clin. Exp. Immunol. 152, 201–210 (2008)

  14. 14

    Finzi, D. & Siliciano, R. F. Viral dynamics in HIV-1 infection. Cell 93, 665–671 (1998)

  15. 15

    Arts, E. J. & Hazuda, D. J. HIV-1 antiretroviral drug therapy. Cold Spring Harb. Persp. Med. 2, a007161 (2012)

  16. 16

    Traggiai, E. et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304, 104–107 (2004)

  17. 17

    Brehm, M. A. et al. Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rγnull mutation. Clin. Immunol. 135, 84–98 (2010)

  18. 18

    Baenziger, S. et al. Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice. Proc. Natl Acad. Sci. USA 103, 15951–15956 (2006)

  19. 19

    Ince, W. L. et al. Evolution of the HIV-1 env gene in the Rag2−/−γC−/− humanized mouse model. J. Virol. 84, 2740–2752 (2010)

  20. 20

    McLellan, J. S. et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011)

  21. 21

    Klein, F. et al. Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J. Exp. Med. 209, 1469–1479 (2012)

  22. 22

    Kwong, P. D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998)

  23. 23

    Mehandru, S. et al. Adjunctive passive immunotherapy in human immunodeficiency virus type 1-infected individuals treated with antiviral therapy during acute and early infection. J. Virol. 81, 11016–11031 (2007)

  24. 24

    Trkola, A. et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nature Med. 11, 615–622 (2005)

  25. 25

    Nimmerjahn, F. & Ravetch, J. V. Antibody-mediated modulation of immune responses. Immunol. Rev. 236, 265–275 (2010)

  26. 26

    Ng, C. T. et al. Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nature Med. 16, 1117–1119 (2010)

  27. 27

    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)

  28. 28

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

  29. 29

    Rouet, F. et al. Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting. J. Clin. Microbiol. 43, 2709–2717 (2005)

  30. 30

    Mouquet, H. Complex-type N-glycan recognition by potent broadly-neutralizing HIV antibodies. Proc. Natl Acad. Sci. USA (in the press)

  31. 31

    Billerbeck, E. et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγnull humanized mice. Blood 117, 3076–3086 (2011)

  32. 32

    Zhang, Y. J. et al. Envelope-dependent, cyclophilin-independent effects of glycosaminoglycans on human immunodeficiency virus type 1 attachment and infection. J. Virol. 76, 6332–6343 (2002)

  33. 33

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

  34. 34

    Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008)

  35. 35

    Montefiori, D. C. Evaluating neutralizing antibodies against HIV, SIV, and SHIV in luciferase reporter gene assays. Curr. Protoc. Immunol. Ch. 12, Unit 12 11. (2005)

  36. 36

    Li, M. et al. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 79, 10108–10125 (2005)

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Acknowledgements

We thank R. Kaiser for analysing viral loads of reference HIV-1 samples and N. N. Freund for producing YU2 gp120. We thank B. Flatley, T. Friling, H. Gao, S. Sell and S. Hinklein for assistance and technical support, M. Suarez-Farinas for advice on statistical analysis, and M. Babayeva for helping with antibody t1/2 estimation. M.C.N. and F.K. have a pending patent application for the antibody 3BC176 and M.C.N., P.J.B. and H.M. for the antibody 10-1074 with the United States Patent and Trademark Office. These reagents are available with a Material Transfer Agreement. F.K. (KL 2389/1-1), M.D. (DO 1450/1-1) and E.B. (BI 1422/1-1) were supported by the German Research Foundation (DFG). H.G., C.G. and R.-B.I. were supported by The German National Academic Foundation. M.S.S. was supported by the Bill and Melinda Gates Foundation’s Comprehensive Antibody Vaccine Immune Monitoring Consortium, grant number 1032144. A.P. is a recipient of a Liver Scholar Award from the American Liver Foundation. This work was supported in part by CAVD grant OPP1033115 from the Bill and Melinda Gates Foundation to M.C.N., in part by NIAID 1UM1AI100663 to M.C.N. and NIH grant AI081677 to M.C.N. M.C.N., P.J.B. and P.D.B. are HHMI investigators.

Author information

F.K., A.H.-S. and J.A.H. planned and performed experiments and wrote the manuscript. H.G., J.F.H., S.B., H.M., L.A.S., R.D., A.A., T.Z., M.D., E.B., R.N.L., C.G., P.M.M., R.-B.I., T.R.E. and M.S.S. performed experiments. P.D.B., P.J.B., J.V.R. and A.P. provided reagents, advice and edited the manuscript. M.C.N. planned experiments and wrote the manuscript.

Correspondence to Michel C. Nussenzweig.

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Klein, F., Halper-Stromberg, A., Horwitz, J. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122 (2012) doi:10.1038/nature11604

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