Abstract

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)1,2. However, even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 μg ml−1), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3,4,5,6. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) < 0.05 μg ml−1). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17–77 μg ml−1 of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

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Acknowledgements

This project was supported by National Institutes of Health (NIH) grants R01 AI091476 and R01 AI080324 (M.F.), P01 AI100263 (G.G., R.C.D., M.F.), RR000168 (M.R.G., L.M.K., D.T.E., R.C.D., M.F.), R01 AI058715 (B.H.H.), by the Intramural Research program of the Vaccine Research Center, NIAID, NIH (J.G., B.Z., P.D.K.), and by federal funds from the National Cancer Institute, NIH under contract no. HHSN261200800001E. The authors would like to thank H. Choe and M. Martin for critical advice.

Author information

Author notes

    • Matthew R. Gardner
    •  & Lisa M. Kattenhorn

    These authors contributed equally to this work.

Affiliations

  1. Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA

    • Matthew R. Gardner
    • , Hema R. Kondur
    • , Tatyana Dorfman
    • , Charles C. Bailey
    • , Christoph H. Fellinger
    • , Vinita R. Joshi
    • , Brian D. Quinlan
    •  & Michael Farzan
  2. Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA

    • Lisa M. Kattenhorn
    • , Jessica J. Chiang
    • , Michael D. Alpert
    • , Ernest S. Neale
    • , Annie Y. Yao
    •  & Ronald C. Desrosiers
  3. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA

    • Markus von Schaewen
    •  & Alexander Ploss
  4. Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA

    • Kevin G. Haworth
    •  & Paula M. Cannon
  5. Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Julie M. Decker
    •  & Beatrice H. Hahn
  6. Immunathon Inc., Cambridge, Massachusetts 02141, USA

    • Michael D. Alpert
  7. Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA

    • Sebastian P. Fuchs
    • , Jose M. Martinez-Navio
    •  & Ronald C. Desrosiers
  8. Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA

    • Hugo Mouquet
    •  & Michel C. Nussenzweig
  9. Department of Immunology, Institut Pasteur, Paris, 75015, France

    • Hugo Mouquet
  10. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Jason Gorman
    • , Baoshan Zhang
    •  & Peter D. Kwong
  11. Department of Immunology and Microbial Science, IAVI Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA

    • Pascal Poignard
    •  & Dennis R. Burton
  12. Howard Hughes Medical Institute, New York, New York 10065, USA

    • Michel C. Nussenzweig
  13. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA

    • Dennis R. Burton
  14. AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA

    • Michael Piatak
    •  & Jeffrey D. Lifson
  15. Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

    • Guangping Gao
  16. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53711, USA

    • David T. Evans
  17. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

    • Michael S. Seaman

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Contributions

M.R.G. and L.M.K. contributed equally to this work. M.R.G., L.M.K., H.R.K., M.V.S., T.D., J.J.C., M.D.A., M.P., J.D.L., R.C.D., D.T.E., B.H.H., P.M.C., M.S.S., A.P. and M.F. designed experiments. M.R.G., L.M.K., H.R.K., M.V.S., T.D., J.J.C., K.G.H., J.M.D., M.D.A., C.C.B., C.H.F., V.R.J., B.D.Q. and A.Y.Y. performed experiments. L.M.K. conducted all non-human primate studies. J.G. and P.D.K. assisted with modelling. J.M.M.-N., H.M., B.Z., P.P., M.S.S., M.C.N. and D.R.B. contributed advice and critical reagents. M.F. conceived the study and, with important assistance from M.R.G. and L.M.K., wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Farzan.

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https://doi.org/10.1038/nature14264

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