title: AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity.
abstract: Long-term delivery of potent broadly-neutralizing antibodies is a promising approach for the prevention of HIV-1 infection. We used AAV vector intramuscularly to deliver anti-SIV monoclonal antibodies (mAbs) in IgG1 form to rhesus monkeys. Persisting levels of delivered mAb as high as 270 μg/ml were achieved. However, host antibody responses to the delivered antibody were observed in 9 of the 12 monkeys and these appeared to limit the concentration of delivered antibody that could be achieved. This is reflected in the wide range of delivered mAb concentrations that were achieved: 1-270 μg/ml. Following repeated, marginal dose, intravenous challenge with the difficult-to-neutralize SIVmac239, the six monkeys in the AAV-5L7 IgG1 mAb group showed clear protective effects despite the absence of detectable neutralizing activity against the challenge virus. The protective effects included: lowering of viral load at peak height; lowering of viral load at set point; delay in the time to peak viral load from the time of the infectious virus exposure. All of these effects were statistically significant. In addition, the monkey with the highest level of delivered 5L7 mAb completely resisted six successive SIVmac239 i.v. challenges, including a final challenge with a dose of 10 i.v. infectious units. Our results demonstrate the continued promise of this approach for the prevention of HIV-1 infection in people. However, the problem of anti-antibody responses will need to be understood and overcome for the promise of this approach to be effectively realized.
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America; Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sebastian P
authors.initials: SP
authors.lastname: Fuchs
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: José M
authors.initials: JM
authors.lastname: Martinez-Navio
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Desrosiers
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D000229:Dependovirus; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology*; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014162:Transfection
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D018449:SAIDS Vaccines