Abstract
Human adenovirus Ad36 increases adiposity in several animal models, including rodents and non-human primates. Importantly, Ad36 is associated with human obesity, which has prompted research to understand its epidemiology and to develop a vaccine to prevent a subgroup of obesity. For this purpose, understanding the genomic stability of Ad36 in vivo and in vitro infections is critical. Here, we examined whether in vitro cell passaging over a 14-year period introduced any genetic variation in Ad36. We sequenced the whole genome of Ad36–which was plaque purified in 1998 from the original strain obtained from American Type Culture Collection, and passaged approximately 12 times over the past 14 years (Ad36-2012). This DNA sequence was compared with a previously published sequence of Ad36 likely obtained from the same source (Ad36-1988). Compared with Ad36-1988, only two nucleotides were altered in Ad36-2012: a T insertion at nucleotide 1862, which may induce early termination of the E1B viral protein, and a T→C transition at nucleotide 26 136. Virus with the T insertion (designated Ad36-2012-T6) was mixed with wild-type virus lacking the T insertion (designated Ad36-2012-T5) in the viral stock. The transition at nucleotide 26 136 does not change the encoded amino acid (aspartic acid) in the pVIII viral protein. The rate of genetic variation in Ad36 is ∼2.37 × 10–6 mutations/nucleotide/passage. Of particular importance, there were no mutations in the E4orf1 gene, the critical gene for producing obesity. This very-low-variation rate should reduce concerns about genetic variability when developing Ad36 vaccines or developing assays for detecting Ad36 infection in populations.
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Acknowledgements
Research funded in part by Vital Health Interventions, to NVD, and by a National Research Foundation of Korea Grant funded by the Korean Government (NRF-2012S1A2A1A01028997), the Catholic University of Korea, Research Fund 2013, and a grant from GRRC of the Catholic University of Korea to J-HN, and by the Beers-Murphy Clinical Nutrition Center at the University of Wisconsin, Madison, USA.
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The following Patents are granted or have been applied by NVD for: Patent number 6 127 113: Viral obesity methods and compositions. Patent number 6 664 050: Viral obesity methods and compositions. Patent number US 8 008 436B2, dated 30 August 2011: Adenovirus 36 E4orf1 gene and protein and their uses. Provisional patent filed: Adenovirus Ad36 E4orf1 protein for prevention and treatment of non-alcoholic fatty liver disease, July 2010. Provisional patent filed: Enhanced glycemic control using Ad36E4orf1 and AKT1 Inhibitor. January 2012. RLA is the owner of Obetech, LLC, a company that provides assays for adenoviruses that produce obesity and owns multiple patents in the area of virus-induced obesity.
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Nam, JH., Na, HN., Atkinson, R. et al. Genomic stability of adipogenic human adenovirus 36. Int J Obes 38, 321–324 (2014). https://doi.org/10.1038/ijo.2013.67
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DOI: https://doi.org/10.1038/ijo.2013.67
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