Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Dennis R. Burton.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing