Fc receptor but not complement binding is important in antibody protection against HIV

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Abstract

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.

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Figure 1: Effector function variants of b12: location of substitutions, antigen binding and neutralization properties.
Figure 2: Interaction of b12 and variants with effector molecules.
Figure 3: Temporal analysis of plasma viral loads.
Figure 4: Antibody-dependent cell-mediated viral inhibition (ADCVI) by b12 and variants.

References

  1. 1

    McMichael, A. J. HIV vaccines. Annu. Rev. Immunol. 24, 227–255 (2006)

  2. 2

    Johnston, M. I. & Fauci, A. S. An HIV vaccine—evolving concepts. N. Engl. J. Med. 356, 2073–2081 (2007)

  3. 3

    Mascola, J. R. Passive transfer studies to elucidate the role of antibody-mediated protection against HIV-1. Vaccine 20, 1922–1925 (2002)

  4. 4

    Veazey, R. S. et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nature Med. 9, 343–346 (2003)

  5. 5

    Parren, P. W. & Burton, D. R. The antiviral activity of antibodies in vitro and in vivo. Adv. Immunol. 77, 195–262 (2001)

  6. 6

    Klasse, P. J. & Sattentau, Q. J. Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J. Gen. Virol. 83, 2091–2108 (2002)

  7. 7

    Burton, D. R. Antibodies, viruses and vaccines. Nature Rev. Immunol. 2, 706–713 (2002)

  8. 8

    Huber, V. C., Lynch, J. M., Bucher, D. J., Le, J. & Metzger, D. W. Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J. Immunol. 166, 7381–7388 (2001)

  9. 9

    Baldridge, J. R. & Buchmeier, M. J. Mechanisms of antibody-mediated protection against lymphocytic choriomeningitis virus infection: mother-to-baby transfer of humoral protection. J. Virol. 66, 4252–4257 (1992)

  10. 10

    Gauduin, M. C., Weir, R., Fung, M. S. & Koup, R. A. Involvement of the complement system in antibody-mediated post-exposure protection against human immunodeficiency virus type 1. AIDS Res. Hum. Retroviruses 14, 205–211 (1998)

  11. 11

    Binley, J. M. et al. Passive infusion of immune serum into simian immunodeficiency virus-infected rhesus macaques undergoing a rapid disease course has minimal effect on plasma viremia. Virology 270, 237–249 (2000)

  12. 12

    Gomez-Roman, V. R. et al. Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J. Immunol. 174, 2185–2189 (2005)

  13. 13

    Florese, R. H. et al. Evaluation of passively transferred, nonneutralizing antibody-dependent cellular cytotoxicity-mediating IgG in protection of neonatal rhesus macaques against oral SIVmac251 challenge. J. Immunol. 177, 4028–4036 (2006)

  14. 14

    Demberg, T. et al. Non-neutralizing antibodies and vaccine-induced protection. Retrovirology 3 (Suppl. 1). S26 (2006)

  15. 15

    Holl, V. et al. Efficient inhibition of HIV-1 replication in human immature monocyte-derived dendritic cells by purified anti-HIV-1 IgG without induction of maturation. Blood 107, 4466–4474 (2006)

  16. 16

    Holl, V. et al. Nonneutralizing antibodies are able to inhibit human immunodeficiency virus type 1 replication in macrophages and immature dendritic cells. J. Virol. 80, 6177–6181 (2006)

  17. 17

    Burton, D. R. et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024–1027 (1994)

  18. 18

    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)

  19. 19

    Parren, P. W. et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro.. J. Virol. 75, 8340–8347 (2001)

  20. 20

    Zhou, T. et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732–737 (2007)

  21. 21

    Hezareh, M., Hessell, A. J., Jensen, R. C., van de Winkel, J. G. & Parren, P. W. Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J. Virol. 75, 12161–12168 (2001)

  22. 22

    Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors: old friends and new family members. Immunity 24, 19–28 (2006)

  23. 23

    Schmitz, J. E. et al. A nonhuman primate model for the selective elimination of CD8+ lymphocytes using a mouse–human chimeric monoclonal antibody. Am. J. Pathol. 154, 1923–1932 (1999)

  24. 24

    Forthal, D. N. et al. Rhesus macaque polyclonal and monoclonal antibodies inhibit simian immunodeficiency virus in the presence of human or autologous rhesus effector cells. J. Virol. 80, 9217–9225 (2006)

  25. 25

    Harouse, J. M. et al. Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3). J. Virol. 75, 1990–1995 (2001)

  26. 26

    Harouse, J. M., Gettie, A., Tan, R. C., Blanchard, J. & Cheng-Mayer, C. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 284, 816–819 (1999)

  27. 27

    Tan, R. C., Harouse, J. M., Gettie, A. & Cheng-Mayer, C. In vivo adaptation of SHIV(SF162): chimeric virus expressing a NSI, CCR5-specific envelope protein. J. Med. Primatol. 28, 164–168 (1999)

  28. 28

    Marx, P. A. et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature Med. 2, 1084–1089 (1996)

  29. 29

    Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100, 4144–4149 (2003)

  30. 30

    Zwick, M. B. et al. Identification and characterization of a peptide that specifically binds the human, broadly neutralizing anti-human immunodeficiency virus type 1 antibody b12. J. Virol. 75, 6692–6699 (2001)

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Acknowledgements

We thank K. Saye-Francisco, P. and C. Carney, R. Aguilar-Sino and D. Tehrani for antibody production assistance at TSRI. We also thank T. Vink for expressing FcγR and the technical assistance of A. van den Broek and A. Ortiz Buijsse at Genmab. We are grateful for the assistance provided by C. Corbaci during the preparation of the manuscript. We also thank M. Zwick and R. Pantophlet for discussions. Support for this work was provided by an NIH grant (D.R.B.), by the Neutralizing Antibody Consortium of the International AIDS Vaccine Initiative, and by a Swiss National Foundation Fellowship (L.H.) and an NIH grant (D.N.F.).

Author Contributions Project planning was performed by A.J.H., L.H., P.W.H.I.P., P.A.M., D.R.B.; experimental work by A.J.H., L.H., M.H., C.E.G.H., F.J.B., G.L., D.N.F.; data analysis by A.J.H., L.H., J.M.B., C.M.S.L., G.L., D.N.F., P.W.H.I.P., P.A.M., D.R.B.; and manuscript composition by A.J.H., L.H., P.W.H.I.P. and D.R.B.

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Correspondence to Dennis R. Burton.

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Competing interests

D.R.B. is listed as an inventor on a patent describing the human neutralizing antibody b12.

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Supplementary Information

This file contains Supplementary Tables 1-4 and Supplementary Figure 1 with Legends. (PDF 1090 kb)

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Hessell, A., Hangartner, L., Hunter, M. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007) doi:10.1038/nature06106

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