title: Episodic Diversifying Selection Shaped the Genomes of Gibbon Ape Leukemia Virus and Related Gammaretroviruses.
abstract: Gibbon ape leukemia viruses (GALVs) are part of a larger group of pathogenic gammaretroviruses present across phylogenetically diverse host species of Australasian mammals. Despite the biomedical utility of GALVs as viral vectors and in cancer gene therapy, full genome sequences have not been determined for all of the five identified GALV strains, nor has a comprehensive evolutionary analysis been performed. We therefore generated complete genomic sequences for each GALV strain using hybridization capture and high-throughput sequencing. The four strains of GALV isolated from gibbons formed a monophyletic clade that was closely related to the woolly monkey virus (WMV), which is a GALV strain that likely originated in a gibbon host. The GALV-WMV clade in turn formed a sister group to the koala retroviruses (KoRVs). Genomic signatures of episodic diversifying selection were detected among the gammaretroviruses with concentration in the env gene across the GALV strains that were particularly oncogenic and KoRV strains that were potentially exogenous, likely reflecting their adaptation to the host immune system. In vitro studies involving vectors chimeric between GALV and KoRV-B established that variable regions A and B of the surface unit of the envelope determine which receptor is used by a viral strain to enter host cells.
  
  
  OBJECTIVE
  The gibbon ape leukemia viruses (GALVs) are among the most medically relevant retroviruses due to their use as viral vectors for gene transfer and in cancer gene therapy. Despite their importance, full genome sequences have not been determined for the majority of primate isolates, nor has comprehensive evolutionary analysis been performed, despite evidence that the viruses are facing complex selective pressures associated with cross-species transmission. Using hybridization capture and high-throughput sequencing, we report here the full genome sequences of all the GALV strains and demonstrate that diversifying selection is acting on them, particularly in the envelope gene in functionally important domains, suggesting that host immune pressure is shaping GALV evolution.
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany.
authors.forename: Niccolò
authors.initials: N
authors.lastname: Alfano
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, New York, USA Sackler Institute for Comparative Genomics and Division of Invertebrate Zoology, American Museum of Natural History, New York, New York, USA.
authors.forename: Sergios-Orestis
authors.initials: SO
authors.lastname: Kolokotronis
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany.
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Tsangaras
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Roca
authors.affiliation: Section on Directed Gene Transfer, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wenqin
authors.initials: W
authors.lastname: Xu
authors.affiliation: Section on Directed Gene Transfer, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Maribeth V
authors.initials: MV
authors.lastname: Eiden
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany greenwood@izw-berlin.de.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Greenwood
mesh_terms: D000818:Animals; D044362:Australasia; D016000:Cluster Analysis; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000235:genetics; D005822:Genetic Vectors; D016679:Genome, Viral; D059014:High-Throughput Nucleotide Sequencing; D006922:Hylobates / Q000821:virology*; D017989:Leukemia Virus, Gibbon Ape / Q000235:genetics*; D008969:Molecular Sequence Data; D048368:Phascolarctidae; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D053586:Virus Internalization
chemical_list: D015686:Gene Products, env; D012367:RNA, Viral