Abstract
The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.
Highlights
Decades of research into the family Adenoviridae has, for the most part, focused on human Ad type 5 (HAdV-5) as a prototype vector, with this providing the basis of our knowledge of Ad receptor/co-receptor usage, host interactions and immunogenicity
To enhance the potential for viral propagation in a standard producer cell line, the human adenovirus (HAdV)-56 E4ORF6 region was exchanged with that of HAdV-5, as this strategy was previously reported to enhance the growth of recombinant Ad vectors in HAdV-5 E1-complementing HEK293 cells [15, 16]
The wild-type (WT) HAdV-56 E4ORF6 region was replaced with that of HAdV-5, a technique that was previously adopted for the generation of HAdV-26, HAdV-48 and HAdV-49 vectors, and enabled their successful production in HAdV-5 E1-complementing cells [13, 15]
Summary
Decades of research into the family Adenoviridae has, for the most part, focused on human Ad type 5 (HAdV-5) as a prototype vector, with this providing the basis of our knowledge of Ad receptor/co-receptor usage, host interactions and immunogenicity. Despite the accumulation of years of clinical trial safety data, the evidence for therapeutic efficacy has been questionable, and this is in large part due to high levels of neutralizing antibodies against HAdV-5 in the general population capable of minimizing the active vector load, and/or poor or irregular expression and exposure of its cellular receptor [coxsackie and adenovirus receptor (CAR)] on cells and tissues of interest [1]. There is a need to find Ad types with low seroprevalence and alternative tropisms in place of HAdV-5, but without compromising on the ease of manufacture and vector yield [7, 8]. Investigation into the in vitro and in vivo 000978 ã 2018 The Authors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
