title: AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.
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.
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gardner
authors.affiliation: Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kattenhorn
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Hema R
authors.initials: HR
authors.lastname: Kondur
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: von Schaewen
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dorfman
authors.affiliation: Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Chiang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Haworth
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.affiliation: 1] Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA [2] Immunathon Inc., Cambridge, Massachusetts 02141, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Alpert
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Bailey
authors.affiliation: Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Neale
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Fellinger
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Vinita R
authors.initials: VR
authors.lastname: Joshi
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Sebastian P
authors.initials: SP
authors.lastname: Fuchs
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Martinez-Navio
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Quinlan
authors.affiliation: Department of Comparative Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
authors.forename: Annie Y
authors.initials: AY
authors.lastname: Yao
authors.affiliation: 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Department of Immunology, Institut Pasteur, Paris, 75015, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Mouquet
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gorman
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.affiliation: 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.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: 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.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Desrosiers
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53711, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Cannon
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D065100:CCR5 Receptor Antagonists / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D015483:HIV Antibodies / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D015498:HIV-2 / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D053586:Virus Internalization
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D015483:HIV Antibodies; D007136:Immunoglobulins; D019713:Receptors, CCR5