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.

A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges

Nature volume 533, pages 105–109 (2016)Cite this article

Subjects

Abstract

Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively1,2,3,4,5,6,7,8, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg−1) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9, 10, 11, 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: HIV MAbs delay virus acquisition after repeated low-dose intrarectal SHIVAD8-EO challenges.
Figure 2: Kaplan–Meier analysis and magnitude of protection by HIV MAbs in repeated low-dose challenge.
Figure 3: Plasma concentrations of the infused MAbs in macaques correlate with long-term protection from SHIV infection.
Figure 4: The decline of neutralizing antibody titres in plasma over time in macaques corresponds to the time of virus acquisition.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. 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)

    Article  CAS  PubMed  Google Scholar 

  3. 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. Nature Med. 6, 207–210 (2000)

    Article  CAS  PubMed  Google Scholar 

  4. Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo . Proc. Natl Acad. Sci. USA 109, 18921–18925 (2012)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. 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 

  7. Pietzsch, J. et al. A mouse model for HIV-1 entry. Proc. Natl Acad. Sci. USA 109, 15859–15864 (2012)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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. Nature Med. 5, 204–210 (1999)

    Article  CAS  PubMed  Google Scholar 

  9. Ko, S. Y. et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514, 642–645 (2014)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mouquet, H. et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc. Natl Acad. Sci. USA 109, E3268–E3277 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burton, D. R. & Mascola, J. R. Antibody responses to envelope glycoproteins in HIV-1 infection. Nature Immunol. 16, 571–576 (2015)

    Article  CAS  Google Scholar 

  14. Barouch, D. H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Klein, F. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122 (2012)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Shingai, M. et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277–280 (2013)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lynch, R. M. et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206 (2015)

    Article  PubMed  Google Scholar 

  19. Rudicell, R. S. et al. Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo . J. Virol. 88, 12669–12682 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  20. Saunders, K. O. et al. Sustained delivery of a broadly neutralizing antibody in nonhuman primates confers long-term protection against simian/human immunodeficiency virus infection. J. Virol. 89, 5895–5903 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shingai, M. et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J. Exp. Med. 211, 2061–2074 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patel, P. et al. Estimating per-act HIV transmission risk: a systematic review. AIDS 28, 1509–1519 (2014)

    Article  PubMed  Google Scholar 

  23. Fiore, A. E., Wasley, A. & Bell, B. P. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbid. Mortal. Wkly Rep. 55, 1–23 (2006)

    Google Scholar 

  24. Graham, B. S. & Ambrosino, D. M. History of passive antibody administration for prevention and treatment of infectious diseases. Curr. Opin. HIV AIDS 10, 129–134 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shingai, M. et al. Most rhesus macaques infected with the CCR5-tropic SHIV(AD8) generate cross-reactive antibodies that neutralize multiple HIV-1 strains. Proc. Natl Acad. Sci. USA 109, 19769–19774 (2012)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nishimura, Y. et al. Generation of the pathogenic R5-tropic simian/human immunodeficiency virus SHIVAD8 by serial passaging in rhesus macaques. J. Virol. 84, 4769–4781 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gautam, R. et al. Pathogenicity and mucosal transmissibility of the R5-tropic simian/human immunodeficiency virus SHIV(AD8) in rhesus macaques: implications for use in vaccine studies. J. Virol. 86, 8516–8526 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. West, A. P. Jr et al. Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues. Proc. Natl Acad. Sci. USA 110, 10598–10603 (2013)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hansen, S. G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ledgerwood, J. E. et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin. Exp. Immunol. 182, 289–301 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Endo, Y. et al. Short- and long-term clinical outcomes in rhesus monkeys inoculated with a highly pathogenic chimeric simian/human immunodeficiency virus. J. Virol. 74, 6935–6945 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei, X. et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob. Agents Chemother. 46, 1896–1905 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Plishka, A. Peach, and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and assisting with procedures. We also thank R. Schwartz for clinical-grade VRC01 and VRC01-LS, and X. Chen for protein reagents for ELISA. We thank the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program for TZM-bl cells. We thank R. Fast for ultrasensitive plasma SIV RNA assays and W. Bosche and M Hull for ultrasensitive peripheral blood mononuclear cell SIV RNA/DNA assays. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and, in part, with federal funds from the National Cancer Institute, NIH, under contract number HHSN261200800001E (to J.D.L.). The research was also funded in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grants OPP1033115 and OPP1092074 (to M.C.Nu.), by the NIH under award numbers AI-100148, UM1 AI100663-01. M.C.Nu. is supported by the Robertson Foundation and the The Howard Hughes Medical Institute.

Author information

Author notes

  1. Rajeev Gautam and Yoshiaki Nishimura: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Rajeev Gautam, Yoshiaki Nishimura, Alicia Buckler-White, Reza Sadjadpour & Malcolm A. Martin

  2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Amarendra Pegu, Keyun Wang, Zachary Mankoff, Stephen D. Schmidt & John R. Mascola

  3. Division of Clinical Research, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Martha C. Nason

  4. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10065, New York, USA

    Florian Klein, Anna Gazumyan, Jovana Golijanin & Michel C. Nussenzweig

  5. Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, 50931, Germany

    Florian Klein

  6. Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, 50937, Germany

    Florian Klein

  7. AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, 21702, Maryland, USA

    Jeffrey D. Lifson

  8. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Michel C. Nussenzweig

Authors
  1. Rajeev Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshiaki Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amarendra Pegu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martha C. Nason
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Florian Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Gazumyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jovana Golijanin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alicia Buckler-White
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Reza Sadjadpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keyun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zachary Mankoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stephen D. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jeffrey D. Lifson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John R. Mascola
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michel C. Nussenzweig
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Malcolm A. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.G., Y.N., M.A.M., M.C.Nu., and J.R.M. designed experiments; R.G., Y.N., A.P., F.K., A.G., J.G., A.B.W., R.S., K.W., Z.M., and S.D.S. performed experiments; R.G., Y.N., M.C.Na., M.A.M., M.C.Nu., J.R.M., and J.D.L. analysed data; R.G., Y.N., M.A.M., M.C.Nu., J.R.M., and J.D.L. wrote the manuscript.

Corresponding author

Correspondence to Malcolm A. Martin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Neutralization sensitivity of SHIVAD8-EO to four broadly acting neutralizing anti-HIV-1 MAbs.

a, Neutralizing activity of the indicated bNAbs was determined against SHIVAD8-EO pseudovirions using TZM-bl target cells. The calculated IC50 and IC80 values are shown at the bottom. b, Neutralizing activity of the indicated bNAbs was determined against replication competent SHIVAD8-EO in a single round TZM-bl infectivity assay. The calculated IC50 and IC80 values are shown at the bottom. The assay was performed in the presence of indinavir. Both experiments were performed twice.

Extended Data Figure 2 Development of anti-MAb immune responses in recipients of anti-HIV-1 bNAbs.

a–d, Longitudinal analysis of anti-VRC01, anti-3BNC117, anti-10-1074, and anti-VRC01-LS antibody responses, respectively, after a single intravenous infusion of indicated MAbs. This assay was performed twice.

Extended Data Figure 3 Predicted probability of infection as a function of antibody levels.

The per-challenge probability of infection was modelled as a function of antibody concentration at the time of each challenge using a probit regression model. The fitted probabilities from the models are plotted separately for each MAb group, with the estimated probability of infection for the control animals (0.27) indicated by the open circle adjacent to each ordinate. The VRC01 and VRC01-LS curves are superimposed. The points on each curve represent the median concentration at the time of breakthrough infection for each group of monkeys.

Extended Data Table 1 Plasma viral RNA and cell-associated viral RNA/DNA in rhesus macaques before breakthrough of infection
Full size table
Extended Data Table 2 VRC01 and 3BNC117 antibody concentrations in the plasma of macaques after a single administration of the indicated MAbs
Full size table
Extended Data Table 3 10-1074 and VRC01-LS antibody concentrations in the plasma of macaques after a single administration of the indicated MAbs
Full size table

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gautam, R., Nishimura, Y., Pegu, A. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016). https://doi.org/10.1038/nature17677

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature17677

This article is cited by

Comments

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.

Search

Advanced 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