Brief Communication | Published:

Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection

Nature Medicine volume 20, pages 13971400 (2014) | Download Citation

Subjects

Abstract

α4β7 integrin–expressing CD4+ T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4+ T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    & Curr. Opin. HIV AIDS 3, 356–361 (2008).

  2. 2.

    et al. J. Exp. Med. 200, 761–770 (2004).

  3. 3.

    et al. Science 280, 427–431 (1998).

  4. 4.

    , & Immunity 3, 99–108 (1995).

  5. 5.

    et al. J. Immunol. 153, 517–528 (1994).

  6. 6.

    et al. Nat. Immunol. 9, 301–309 (2008).

  7. 7.

    , , , & PLoS ONE 7, e39045 (2012).

  8. 8.

    et al. PLoS Pathog. 7, e1001301 (2011).

  9. 9.

    et al. Cell. Immunol. 259, 165–176 (2009).

  10. 10.

    et al. J. Immunol. 186, 1044–1059 (2011).

  11. 11.

    et al. Blood 118, 2763–2773 (2011).

  12. 12.

    & Infect. Immun. 65, 5198–5208 (1997).

  13. 13.

    et al. Proc. Natl. Acad. Sci. USA 106, 20877–20882 (2009).

  14. 14.

    et al. Mucosal Immunol. 2, 439–449 (2009).

  15. 15.

    et al. J. Acquir. Immune Defic. Syndr. 64, 325–331 (2013).

  16. 16.

    et al. J. Immunol. 187, 6032–6042 (2011).

  17. 17.

    et al. N. Engl. J. Med. 369, 699–710 (2013).

  18. 18.

    & Curr. Drug Targets 14, 1433–1443 (2013).

  19. 19.

    et al. N. Engl. J. Med. 369, 711–721 (2013).

  20. 20.

    et al. Ann. Intern. Med. 160, 704–711 (2014).

  21. 21.

    et al. BMC Genomics 12, 295 (2011).

  22. 22.

    et al. Immunogenetics 61, 689–701 (2009).

  23. 23.

    et al. PLoS Pathog. 6, e1000738 (2010).

  24. 24.

    , & Immunogenetics 63, 351–362 (2011).

  25. 25.

    et al. AIDS Res. Hum. Retroviruses 29, 1091–1094 (2013).

  26. 26.

    et al. J. Med. Primatol. 36, 238–243 (2007).

  27. 27.

    et al. J. Immunol. 186, 1044–1059 (2011).

  28. 28.

    & Biometrics 65, 1223–1232 (2009).

  29. 29.

    , , & PLoS Med. 2, e249 (2005).

  30. 30.

    et al. J. Virol. 81, 12368–12374 (2007).

  31. 31.

    et al. J. Acquir. Immune Defic. Syndr. 53, 574–581 (2010).

  32. 32.

    , , & Curr. HIV Res. 10, 79–87 (2012).

  33. 33.

    , , , & PLoS ONE 7, e52992 (2012).

  34. 34.

    et al. J. Immunol. 187, 6032–6042 (2011).

  35. 35.

    et al. Cell. Immunol. 259, 165–176 (2009).

  36. 36.

    et al. Nat. Immunol. 9, 301–309 (2008).

Download references

Acknowledgements

This work was supported by a grant from the NIH-NIAID AI-098628-01 (to A.A.A.), the NIAID NIH Intramural Research Program and OD 51POD1113 to the Yerkes National Primate Research Center. We are grateful to F. Connor-Stroud for help with the cytobrush studies and to the veterinary staff and animal caretakers of the Yerkes National Primate Center of Emory University, specially S. Ehnert and her team. The authors also acknowledge the assistance of M. Piatak for performing the ultrasensitive PCR analysis and R. Kaul and L.R. McKinnon for sharing with us their finding on cervical brush analyses in Africa and advising us on how to proceed in adapting their human findings to our nonhuman primates. Recombinant mAbs were produced by the Nonhuman Primate Reagent Resource (NIAID, NIH contract # HHSN272200900037C). The virus stock of SIVmac251 was obtained courtesy of N. Miller (NIAID, NIH). We apologize to all the authors whose publications we failed to cite. The findings in this report are those of the authors and do not necessarily reflect the views of the US Centers for Disease Control and Prevention.

Author information

Author notes

    • Siddappa N Byrareddy
    •  & Brianne Kallam

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Siddappa N Byrareddy
    • , Brianne Kallam
    • , Ann E Mayne
    • , Paul Dunbar
    • , Tara Villinger
    • , Dawn Little
    • , Tristram G Parslow
    • , Francois Villinger
    •  & Aftab A Ansari
  2. Laboratory of Immunoregulation, National Institute of Allergy & Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • James Arthos
    • , Claudia Cicala
    • , Fatima Nawaz
    • , Joseph Hiatt
    •  & Anthony S Fauci
  3. Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

    • Ellen N Kersh
    • , Janet M McNicholl
    •  & Debra Hanson
  4. Mass Biologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.

    • Keith A Reimann
  5. Primate Genetics Laboratory, German Primate Center, Leibniz-Institute for Primate Research, Göttingen, Germany.

    • Markus Brameier
    •  & Lutz Walter
  6. Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.

    • Kenneth Rogers
    •  & Francois Villinger
  7. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.

    • Philip J Santangelo

Authors

  1. Search for Siddappa N Byrareddy in:

  2. Search for Brianne Kallam in:

  3. Search for James Arthos in:

  4. Search for Claudia Cicala in:

  5. Search for Fatima Nawaz in:

  6. Search for Joseph Hiatt in:

  7. Search for Ellen N Kersh in:

  8. Search for Janet M McNicholl in:

  9. Search for Debra Hanson in:

  10. Search for Keith A Reimann in:

  11. Search for Markus Brameier in:

  12. Search for Lutz Walter in:

  13. Search for Kenneth Rogers in:

  14. Search for Ann E Mayne in:

  15. Search for Paul Dunbar in:

  16. Search for Tara Villinger in:

  17. Search for Dawn Little in:

  18. Search for Tristram G Parslow in:

  19. Search for Philip J Santangelo in:

  20. Search for Francois Villinger in:

  21. Search for Anthony S Fauci in:

  22. Search for Aftab A Ansari in:

Contributions

The day-to-day scheduling of the experiments were carried out under the laboratory supervision of A.E.M., technically performed by S.N.B., B.K., P.D., T.V. and D.L. The experiments described in Figure 2d–h were performed by F.N. and J.H. The overall planning and direction of the studies was carried out by A.A.A. C.C., F.V. and P.J.S. in regularly scheduled consultation with E.N.K., J.M.M. and T.G.P. D.H. provided the statistical planning of the studies and performed the statistical analyses of the data obtained. K.A.R. consulted and provided the large-scale preparation of the recombinant α4β7 monoclonal antibody and the normal rhesus IgG mAbs. M.B. and L.W. performed the major histocompatibility complex typing of the animals, and K.R. performed the Fc receptor typing of the animals. A.A.A. and T.G.P. prepared the draft of this manuscript with input from all the authors. A.S.F. provided helpful discussions and review and revision of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Aftab A Ansari.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Tables 1 and 2

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.3715

Further reading