1887

Journal of General Virology header logo

Volume 98, Issue 10

The integration of a macrophage-adapted live vaccine strain of equine infectious anaemia virus (EIAV) in the horse genome Free

Abstract

Integration is an important feature of retroviruses and retrovirus-based therapeutic transfection vectors. The non-primate lentivirus equine infectious anaemia virus (EIAV) primarily targets macrophages/monocytes . Investigation of the integration features of EIAV strains, which are adapted to donkey monocyte-derived macrophages (MDMs), is of great interest. In this study, we analysed the integration features of EIAV in equine MDMs during infection. Our previously published integration sites (IS) for EIAV in fetal equine dermal (FED) cells were also analysed in parallel as references. Sequencing of the host genomic regions flanking the viral IS showed that reference sequence (RefSeq) genes were preferentially targeted for integration by EIAV. Introns, AT-rich regions, long interspersed nuclear elements (LINEs) and DNA transposons were also predominantly biased toward viral insertion, which is consistent with EIAV integration into the horse genome in FED cells. In addition, the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, specifically gag junctions for EIAV and tight junctions for EIAV, are regulators of metabolic function, which is consistent with the common bioprocesses, specifically cell cycle and chromosome/DNA organization, identified by gene ontology (GO) analysis. Our results demonstrate that EIAV integration occurs in regions that harbour structural and topological features of local chromatin in both macrophages and fibroblasts. Our data on EIAV will facilitate further understanding of lentivirus infection and the development of safer and more effective gene therapy vectors.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): EIAV , integration sites , lentivirus , LINEs , macrophages and RefSeq genes
© 2017 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000918
2017-10-01
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/10/2596.html?itemId=/content/journal/jgv/10.1099/jgv.0.000918&mimeType=html&fmt=ahah

References

  1. Schröder AR, Shinn P, Chen H, Berry C, Ecker JR et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110:521–529 [View Article][PubMed]
     [Google Scholar]
  2. De Ravin SS, Su L, Theobald N, Choi U, Macpherson JL et al. Enhancers are major targets for murine leukemia virus vector integration. J Virol 2014; 88:4504–4513 [View Article][PubMed]
     [Google Scholar]
  3. Trobridge GD, Miller DG, Jacobs MA, Allen JM, Kiem HP et al. Foamy virus vector integration sites in normal human cells. Proc Natl Acad Sci USA 2006; 103:1498–1503 [View Article][PubMed]
     [Google Scholar]
  4. Lafave MC, Varshney GK, Gildea DE, Wolfsberg TG, Baxevanis AD et al. MLV integration site selection is driven by strong enhancers and active promoters. Nucleic Acids Res 2014; 42:4257–4269 [View Article][PubMed]
     [Google Scholar]
  5. Busschots K, Vercammen J, Emiliani S, Benarous R, Engelborghs Y et al. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J Biol Chem 2005; 280:17841–17847 [View Article][PubMed]
     [Google Scholar]
  6. Cherepanov P. LEDGF/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro . Nucleic Acids Res 2007; 35:113–124 [View Article][PubMed]
     [Google Scholar]
  7. Sharma A, Larue RC, Plumb MR, Malani N, Male F et al. BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc Natl Acad Sci USA 2013; 110:12036–12041 [View Article][PubMed]
     [Google Scholar]
  8. De Rijck J, De Kogel C, Demeulemeester J, Vets S, El Ashkar S et al. The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. Cell Rep 2013; 5:886–894 [View Article][PubMed]
     [Google Scholar]
  9. Leroux C, Cadoré JL, Montelaro RC. Equine infectious anemia virus (EIAV): what has HIV's country cousin got to tell us?. Vet Res 2004; 35:485–512 [View Article][PubMed]
     [Google Scholar]
  10. Sellon DC, Perry ST, Coggins L, Fuller FJ. Wild-type equine infectious anemia virus replicates in vivo predominantly in tissue macrophages, not in peripheral blood monocytes. J Virol 1992; 66:5906–5913[PubMed]
     [Google Scholar]
  11. Oaks JL, Ulibarri C, Crawford TB. Endothelial cell infection in vivo by equine infectious anaemia virus. J Gen Virol 1999; 80:2393–2397 [View Article][PubMed]
     [Google Scholar]
  12. Shen RX, Xu ZD, He XS, Zhang SX. Study on immunological methods of equine infectious anemia. China Agric Sci 1979; 4:1–15
     [Google Scholar]
  13. Craigo JK, Montelaro RC. Lessons in AIDS vaccine development learned from studies of equine infectious, anemia virus infection and immunity. Viruses 2013; 5:2963–2976 [View Article][PubMed]
     [Google Scholar]
  14. Honeycutt JB, Thayer WO, Baker CE, Ribeiro RM, Lada SM et al. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat Med 2017; 23:638–643 [View Article][PubMed]
     [Google Scholar]
  15. Shen RX, Wang Z. Development and use of an equine infectious anemia donkey leucocyte attenuated vaccine. EIAV: a national review of policies, programs, and future objectives. American Quarter Horse Association, Amarillo, Tex 1985
  16. Hacker CV, Vink CA, Wardell TW, Lee S, Treasure P et al. The integration profile of EIAV-based vectors. Mol Ther 2006; 14:536–545 [View Article][PubMed]
     [Google Scholar]
  17. Liu Q, Wang XF, Ma J, He XJ, Wang XJ et al. Characterization of equine infectious anemia virus integration in the horse genome. Viruses 2015; 7:3241–3260 [View Article][PubMed]
     [Google Scholar]
  18. Carpenter S, Chesebro B. Change in host cell tropism associated with in vitro replication of equine infectious anemia virus. J Virol 1989; 63:2492–2496[PubMed]
     [Google Scholar]
  19. Ciuffi A, Bushman FD. Retroviral DNA integration: HIV and the role of LEDGF/p75. Trends Genet 2006; 22:388–395 [View Article][PubMed]
     [Google Scholar]
  20. Derse D, Crise B, Li Y, Princler G, Lum N et al. Human T-cell leukemia virus type 1 integration target sites in the human genome: comparison with those of other retroviruses. J Virol 2007; 81:6731–6741 [View Article][PubMed]
     [Google Scholar]
  21. Berry C, Hannenhalli S, Leipzig J, Bushman FD. Selection of target sites for mobile DNA integration in the human genome. PLoS Comput Biol 2006; 2:e157 [View Article][PubMed]
     [Google Scholar]
  22. Holman AG, Coffin JM. Symmetrical base preferences surrounding HIV-1, avian sarcoma/leukosis virus, and murine leukemia virus integration sites. Proc Natl Acad Sci USA 2005; 102:6103–6107 [View Article][PubMed]
     [Google Scholar]
  23. Voigt K, Izsvák Z, Ivics Z. Targeted gene insertion for molecular medicine. J Mol Med 2008; 86:1205–1219 [View Article][PubMed]
     [Google Scholar]
  24. Mitchell RS, Beitzel BF, Schroder AR, Shinn P, Chen H et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2:e234 [View Article][PubMed]
     [Google Scholar]
  25. Maldarelli F, Wu X, Su L, Simonetti FR, Shao W et al. HIV latency. specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 2014; 345:179–183 [View Article][PubMed]
     [Google Scholar]
  26. Shan L, Yang HC, Rabi SA, Bravo HC, Shroff NS et al. Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model. J Virol 2011; 85:5384–5393 [View Article][PubMed]
     [Google Scholar]
  27. Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C et al. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol 2005; 79:6610–6619 [View Article][PubMed]
     [Google Scholar]
  28. Cohn LB, Silva IT, Oliveira TY, Rosales RA, Parrish EH et al. HIV-1 integration landscape during latent and active infection. Cell 2015; 160:420–432 [View Article][PubMed]
     [Google Scholar]
  29. Ciuffi A, Mohammadi P, Golumbeanu M, di Iulio J, Telenti A. Bioinformatics and HIV latency. Curr HIV/AIDS Rep 2015; 12:97–106 [View Article][PubMed]
     [Google Scholar]
  30. Sherrill-Mix S, Lewinski MK, Famiglietti M, Bosque A, Malani N et al. HIV latency and integration site placement in five cell-based models. Retrovirology 2013; 10:90 [View Article][PubMed]
     [Google Scholar]
  31. Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S et al. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol 2004; 78:6122–6133 [View Article][PubMed]
     [Google Scholar]
  32. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC et al. Initial sequencing and analysis of the human genome. Nature 2001; 409:860–921 [View Article][PubMed]
     [Google Scholar]
  33. Desfarges S, Ciuffi A. Retroviral integration site selection. Viruses 2010; 2:111–130 [View Article][PubMed]
     [Google Scholar]
  34. Coppieters F, Lefever S, Leroy BP, De Baere E. CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Hum Mutat 2010; 31:1097–1108 [View Article][PubMed]
     [Google Scholar]
  35. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA 2008; 105:4242–4246 [View Article][PubMed]
     [Google Scholar]
  36. Dieudonné M, Maiuri P, Biancotto C, Knezevich A, Kula A et al. Transcriptional competence of the integrated HIV-1 provirus at the nuclear periphery. Embo J 2009; 28:2231–2243 [View Article][PubMed]
     [Google Scholar]
  37. Huang J, Zhao Y, Shiraigol W, Li B, Bai D et al. Analysis of horse genomes provides insight into the diversification and adaptive evolution of karyotype. Sci Rep 2014; 4:4958 [View Article][PubMed]
     [Google Scholar]
  38. Han JS, Szak ST, Boeke JD. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 2004; 429:268–274 [View Article][PubMed]
     [Google Scholar]
  39. Ustyugova SV, Lebedev YB, Sverdlov ED. Long L1 insertions in human gene introns specifically reduce the content of corresponding primary transcripts. Genetica 2006; 128:261–272 [View Article][PubMed]
     [Google Scholar]
  40. Giepmans BN. Gap junctions and connexin-interacting proteins. Cardiovasc Res 2004; 62:233–245 [View Article][PubMed]
     [Google Scholar]
  41. Schneeberger EE, Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 2004; 286:C1213–C1228 [View Article][PubMed]
     [Google Scholar]
  42. Rezaei SD, Cameron PU. Human immunodeficiency virus (HIV)-1 integration sites in viral latency. Curr HIV/AIDS Rep 2015; 12:88–96 [View Article][PubMed]
     [Google Scholar]
  43. Marini B, Kertesz-Farkas A, Ali H, Lucic B, Lisek K et al. Nuclear architecture dictates HIV-1 integration site selection. Nature 2015; 521:227–231 [View Article][PubMed]
     [Google Scholar]
  44. Serrao E, Krishnan L, Shun MC, Li X, Cherepanov P et al. Integrase residues that determine nucleotide preferences at sites of HIV-1 integration: implications for the mechanism of target DNA binding. Nucleic Acids Res 2014; 42:5164–5176 [View Article][PubMed]
     [Google Scholar]
  45. Schaller T, Ocwieja KE, Rasaiyaah J, Price AJ, Brady TL et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog 2011; 7:e1002439 [View Article][PubMed]
     [Google Scholar]
  46. Lewinski MK, Yamashita M, Emerman M, Ciuffi A, Marshall H et al. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2006; 2:e60 [View Article][PubMed]
     [Google Scholar]
  47. Wang XF, Lin YZ, Li Q, Liu Q, Zhao WW et al. Genetic evolution during the development of an attenuated EIAV vaccine. Retrovirology 2016; 13:9 [View Article][PubMed]
     [Google Scholar]
  48. Binley K, Widdowson P, Loader J, Kelleher M, Iqball S et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease. Invest Ophthalmol Vis Sci 2013; 54:4061–4071 [View Article][PubMed]
     [Google Scholar]
  49. Zallocchi M, Binley K, Lad Y, Ellis S, Widdowson P et al. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat. PLoS One 2014; 9:e94272 [View Article][PubMed]
     [Google Scholar]
  50. Lin YZ, Cao XZ, Li L, Li L, Jiang CG et al. The pathogenic and vaccine strains of equine infectious anemia virus differentially induce cytokine and chemokine expression and apoptosis in macrophages. Virus Res 2011; 160:274–282 [View Article][PubMed]
     [Google Scholar]
  51. Morrow CD, Park J, Wakefield JK. Viral gene products and replication of the human immunodeficiency type 1 virus. Am J Physiol 1994; 266:C1135–1156[PubMed]
     [Google Scholar]
  52. Ranki A, Lagerstedt A, Ovod V, Aavik E, Krohn KJ. Expression kinetics and subcellular localization of HIV-1 regulatory proteins Nef, Tat and Rev in acutely and chronically infected lymphoid cell lines. Arch Virol 1994; 139:365–378 [View Article][PubMed]
     [Google Scholar]
  53. Ciuffi A, Ronen K, Brady T, Malani N, Wang G et al. Methods for integration site distribution analyses in animal cell genomes. Methods 2009; 47:261–268 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000918
Loading
The integration of a macrophage-adapted live vaccine strain of equine infectious anaemia virus (EIAV) in the horse genome
J. Gen. Virol. 98, 2596 (2017); https://doi.org/10.1099/jgv.0.000918
/content/journal/jgv/10.1099/jgv.0.000918
/content/journal/jgv/10.1099/jgv.0.000918
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error