Evolution of dependoparvoviruses across geological timescales – implications for design of AAV-based gene therapy vectors

Hildebrandt, E., Penzes, J. J., Gifford, R. J. , Agbandje-Mckenna, M. and Kotin, R. M. (2020) Evolution of dependoparvoviruses across geological timescales – implications for design of AAV-based gene therapy vectors. Virus Evolution, 6(2), veaa043. (doi: 10.1093/ve/veaa043) (PMID:32913662) (PMCID:PMC7474932)

Abstract

Endogenous viral elements (EVEs) are genetic remnants of viruses that have integrated into host genomes millions of years ago and retained as heritable elements passed on to offspring until present-day. As a result, EVEs provide an opportunity to analyze the genomes of extinct viruses utilizing these genomic viral fossils to study evolution of viruses over large timescales. Analysis of sequences from near full-length EVEs of dependoparvoviral origin identified within three mammalian taxa, Whippomorpha (whales and hippos), Vespertillionade (smooth-nosed bats), and Lagomorpha (rabbits, hares, and pikas), indicates that distinct ancestral dependoparvovirus species integrated into these host genomes approximately 77-23 million years ago (MYA). These ancestral viruses are unique relative to modern adeno-associated viruses (AAVs), and distinct from extant species of genus Dependoparvovirus. These EVE sequences show characteristics previously unseen in modern, mammalian AAVs, but instead appear more similar to the more primitive, autonomously-replicating and pathogenic waterfowl dependoparvoviruses. Phylogeny reconstruction suggests that the whippomorph EVE orthologue derives from exogenous ancestors of autonomous and highly pathogenic dependoparvovirus lineages, believed to have uniquely co-evolved with waterfowl birds to present date. In contrast, ancestors of the two other mammalian orthologues (Lagomorpha and Vespertilionidae) likely shared the same lineage as all other known mammalian exogenous AAVs. Comparative in silico analysis of the EVE genomes revealed remarkable overall conservation of AAV rep and cap genes, despite millions of years of integration within the host germline. Modeling these proteins identified unexpected variety, even between orthologues, in previously defined capsid viral protein (VP) variable regions (VRs), especially in those related to the threefold and fivefold symmetry axes of the capsid. Moreover, the normally well-conserved phospholipase A2 (PLA2) domain of the predicted minor VP1 also exhibited a high degree of sequence variance. These findings may indicate unique biological properties for these virus “fossils” relative to extant dependoparvoviruses and suggest key regions to explore within capsid sequences that may confer novel properties for engineered gene therapy vectors based upon paleovirology data.

• Item Type: Articles
• Additional Information: E.H. and R.M.K were supported by funding from the Association Monégasque Contre les Myopathies. M.A.-M. and J.J.P. were funded by NIH R01 GM109524 and GM082946. R.M.K was supported by the Bill & Melinda Gates Foundation (OPP1202116).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gifford, Dr Robert
• Authors: Hildebrandt, E., Penzes, J. J., Gifford, R. J., Agbandje-Mckenna, M., and Kotin, R. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Virus Evolution
• Publisher: Oxford University Press
• ISSN: 2057-1577
• ISSN (Online): 2057-1577
• Published Online: 22 May 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Virus Evolution 6(2): veaa043
• Publisher Policy: Reproduced under a Creative Commons License