title: Type I interferon-dependent activation of NK cells by rAd28 or rAd35, but not rAd5, leads to loss of vector-insert expression.
abstract: Vaccines constructed from rare-serotype recombinant adenovirus vectors (rAd) such as rAd serotype 28 (rAd28) and rAd35 are currently being explored as alternatives to rAd5-based vaccines because they circumvent the problems with pre-existing immunity that complicate the effectiveness of rAd5 vaccines. However, previous work has demonstrated that the immunogenicity of rAd28 and rAd35 is substantially lower than rAd5. Here we show that rAd28 and rAd35 increase apoptosis of antigen presenting cells (APCs), such as monocytes, relative to rAd5 and mock infected controls. APCs undergoing apoptosis showed an increased loss of vector-insert expression. Loss of vector-insert expression correlated with activation of NK cells, which resulted in apoptosis of co-cultured monocytes. Finally, we show that activation of NK cells is dependent on IFNα which is produced by exposure to rAd28 or rAd35, but not to rAd5. Taken together, these data demonstrate that IFNα-induced activation of NK cells leads to increased monocyte apoptosis and subsequent vector-insert loss. This may be a possible mechanism that results in reduced immunogenicity of rAd28 and rAd35-based vectors.
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors: Matthew J
authors: MJ
authors: Johnson
authors: Pathology Department, Center for Infectious Medicine, Karolinska Institutet, Stockholm 14186, Sweden; Department of Medicine, Karolinska Institutet, Stockholm 14186, Sweden.
authors: Niklas K
authors: NK
authors: Björkström
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Constantinos
authors: C
authors: Petrovas
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Pathology Department, Center for Infectious Medicine, Karolinska Institutet, Stockholm 14186, Sweden; Department of Medicine, Karolinska Institutet, Stockholm 14186, Sweden.
authors: Frank
authors: F
authors: Liang
authors: GenVec, Inc., Gaithersburg, MD 20878, USA.
authors: Jason G D
authors: JG
authors: Gall
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Pathology Department, Center for Infectious Medicine, Karolinska Institutet, Stockholm 14186, Sweden; Department of Medicine, Karolinska Institutet, Stockholm 14186, Sweden.
authors: Karin
authors: K
authors: Loré
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rkoup@mail.nih.gov.
authors: Richard A
authors: RA
authors: Koup
mesh_terms: D000256:Adenoviridae; D017209:Apoptosis; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D009000:Monocytes / Q000166:cytology*
chemical_list: D016898:Interferon-alpha; D018950:Lipopolysaccharide Receptors
keywords: Adenovirus; rAd28; rAd35