Skip to main content

Thank you for visiting nature.com. 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.

Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques

Abstract

Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required1. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus2,3,4. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus–HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function–deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody–treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Viral loads in antibody-treated macaques during vaginal low-dose repeated challenge with SHIVSF162P3.
Figure 2: Kaplan-Meier analysis and magnitude of protection by b12 and LALA treatment in low-dose (10TCID50) repeated challenge.

References

  1. Mascola, J.R. Defining the protective antibody response for HIV-1. Curr. Mol. Med. 3, 209–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. 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  PubMed  Google Scholar 

  3. Hollingsworth, T.D., Anderson, R.M. & Fraser, C. HIV-1 transmission, by stage of infection. J. Infect. Dis. 198, 687–693 (2008).

    Article  PubMed  Google Scholar 

  4. Royce, R.A., Sena, A., Cates, W. Jr. & Cohen, M.S. Sexual transmission of HIV. N. Engl. J. Med. 336, 1072–1078 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Gauduin, M.C. et al. Passive immunization with a human monoclonal antibody protects hu-PBL-SCID mice against challenge by primary isolates of HIV-1. Nat. Med. 3, 1389–1393 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Shibata, R. et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat. Med. 5, 204–210 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mascola, J.R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Baba, T.W. et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6, 200–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nishimura, Y. et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J. Virol. 76, 2123–2130 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chakraborty, H. et al. Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model. AIDS 15, 621–627 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Pilcher, C.D. et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J. Infect. Dis. 189, 1785–1792 (2004).

    Article  PubMed  Google Scholar 

  14. Otten, R.A. et al. Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates. J. Infect. Dis. 191, 164–173 (2005).

    Article  PubMed  Google Scholar 

  15. Klasse, P.J., Shattock, R.J. & Moore, J.P. Which topical microbicides for blocking HIV-1 transmission will work in the real world? PLoS Med. 3, e351 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kim, C.N. et al. Repetitive exposures with simian/human immunodeficiency viruses: strategy to study HIV pre-clinical interventions in non-human primates. J. Med. Primatol. 35, 210–216 (2006).

    Article  PubMed  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).

    Article  CAS  PubMed  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hessell, A.J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Subbarao, S. et al. Direct stringency comparison of two macaque models (single-high vs. repeat-low) for mucosal HIV transmission using an identical anti-HIV chemoprophylaxis intervention. J. Med. Primatol. 36, 238–243 (2007).

    Article  PubMed  Google Scholar 

  22. Regoes, R.R., Longini, I.M., Feinberg, M.B. & Staprans, S.I. Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges. PLoS Med. 2, e249 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dhillon, A.K. et al. Dissecting the neutralizing antibody specificities of broadly neutralizing sera from HIV-1 infected donors. J. Virol. 81, 6548–6562 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li, Y. et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat. Med. 13, 1032–1034 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sather, D.N. et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J. Virol. 83, 757–769 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Doria-Rose, N.A. et al. Frequency and phenotype of human immunodeficiency virus envelope-specific B cells from patients with broadly cross-neutralizing antibodies. J. Virol. 83, 188–199 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Li, Y. et al. Analysis of neutralization specificities in polyclonal sera derived from human immunodeficiency virus type 1-infected individuals. J. Virol. 83, 1045–1059 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Friedrich, T.C. et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. J. Virol. 81, 3465–3476 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cline, A.N., Bess, J.W., Piatak, M. Jr. & Lifson, J.D. Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations and application to reverse engineering of vaccines for AIDS. J. Med. Primatol. 34, 303–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yant, L.J. et al. The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J. Virol. 80, 5074–5077 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaizu, M. et al. Molecular typing of major histocompatibility complex class I alleles in the Indian rhesus macaque which restrict SIV CD8+ T cell epitopes. Immunogenetics 59, 693–703 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

ELISA for recombinant monomeric HIV-1 gp120JR-FL was provided by Progenics. We thank K. Saye-Francisco for antibody production and quality control assistance at The Scripps Research Institute and S. Hoffenberg at the IAVI AIDS Vaccine Design Laboratory. We thank A. Haahr Andreasen for statistical advice and analysis. We are grateful for the assistance provided by E. Rakasz, G. Borchardt, and C. McNair with genotyping and viral load assessments at the Wisconsin National Primate Research Center. We also thank M. Huber and R. Astronomo for reviewing the manuscript. Support for this work was provided by US National Institutes of Health (NIH) grant AI55332 to D.R.B., by the Neutralizing Antibody Consortium of the International AIDS Vaccine Initiative and by the Swiss National Foundation, Fellowship PA00A-109033.

Author information

Authors and Affiliations

Authors

Contributions

Project planning was performed by A.J.H., L.H., P.A.M. and D.R.B.; experimental work was done by A.J.H., L.H., M.H. and D.M.T.; data analysis was done by A.J.H., L.H., P.P., W.K.B., P.W.H.I.P. and D.R.B.; and A.J.H., P.P., P.W.H.I.P. and D.R.B. composed the manuscript.

Ethics declarations

Competing interests

D.R.B. is listed as an inventor on patents describing the human neutralizing antibody b12. These patents include Australia Patent No. 681360, Patent Co-operation Treaty (PCT) Patent No. WO 94/07922, US Patent No. 5,652,138, Australia Patent No. 706601, US Patent No. 5,804,440 and PCT Patent No. WO 96/02273. Patents with the patent offices of Canada, the EU, Finland, Japan and Norway are pending. D.R.B. is also listed on patents describing the synthetic human neutralizing antibody, including the continuation-in-part PCT Patent No. 95/11317 and patents pending in the patent offices of Canada, the EU and Japan.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4 and Supplementary Tables 1–3 (PDF 868 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hessell, A., Poignard, P., Hunter, M. et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat Med 15, 951–954 (2009). https://doi.org/10.1038/nm.1974

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1974

This article is cited by

Search

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