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Nature. 2015 Mar 5;519(7541):87-91. doi: 10.1038/nature14264. Epub 2015 Feb 18.

AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.

Author information

1
Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
2
Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
3
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
4
Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
5
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
6
1] Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA [2] Immunathon Inc., Cambridge, Massachusetts 02141, USA.
7
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
8
1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Department of Immunology, Institut Pasteur, Paris, 75015, France.
9
Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
10
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.
11
1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA.
12
1] 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 [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
13
AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
14
Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
15
1] Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA [2] Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
16
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53711, USA.
17
Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

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). 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 protection. 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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PMID:
25707797
PMCID:
PMC4352131
DOI:
10.1038/nature14264
[Indexed for MEDLINE]
Free PMC Article

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