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2007Murciaphd.Pdf https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] LATE RESTRICTION INDUCED BY AN ENDOGENOUS RETROVIRUS Pablo Ramiro Murcia August 2007 Thesis presented to the School of Veterinary Medicine at the University of Glasgow for the degree of Doctor of Philosophy Institute of Comparative Medicine 464 Bearsden Road Glasgow G61 IQH ©Pablo Murcia ProQuest Number: 10390741 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10390741 Published by ProQuest LLO (2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346 , 'Mmw , Î^TATî’' T , i - T n r . ^ j Abstract Exogenous retroviruses (i.e. horizontally transmitted) must integrate their pro viral DNA into the host’s genome as part of the retroviral cycle. Therefore, infections of the germ line can give rise to vertically transmitted endogenous retroviruses (ERVs). ERVs are present in all vertebrates. During evolution, most ERVs have accumulated mutations and/or deletions that hampered their ability to replicate and hence to harm the host. However, some ERVs have retained at least some of their open reading frames intact even after several million years. One possible reason for the selection of ERVs is that they protected the host against incoming pathogenic exogenous retroviruses. The fact that the vast majority of ERVs do not possess circulating exogenous counterparts supports this view. Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer of sheep caused by a Betaretrovirus known as Jaagsiekte sheep retrovirus (JSRV). Notably, the sheep genome possesses approximately 30 ERVs highly related to JSRV (and hence referred to as enJSRVs). A specific en JSRV provirus, termed enJS56Al, acts as a transdominant restriction factor that blocks the exogenous JSRV at late stages of the replication cycle. The main determinant of this block (termed JLR for JSRV /ate restriction) has been mapped to the N-terminal region of the Gag polyprotein, more precisely to residue 21 of the matrix protein. In this study, the molecular basis of JLR was investigated by functionally characterizing the JSRV and enJS56Al Gag polyproteins. Putative Gag trafficking signals, such as membrane binding (M) and late domains (L) were identified, although it was determined that these domains lack any involvement in JLR. enJS56Al~ expression constructs bearing truncated Gags were unable to block JSRV, indicating that an intact Gag polyprotein is required for JLR. Moreover, intracellular colocalization and protein-protein interaction between JSRV and enJS56Al Gag molecules was determined by confocal microscopy and co-immunoprecipitation, respectively. Complementation assays suggest that JSRV and enJS56Al Gag likely co-assemble. These data are supported by the fact that deletion of the major homology region of enJS56Al Gag allows JSRV to escape JLR. Confocal microscopy experiments indicate that JSRV must reach the pericentriolar region as part of its normal cell cycle and that JLR takes place before this stage. This work unveils basic aspects of JSRV biology that were previously unknown. It also provides insight on the molecular basis of JLR, highlighting the dynamic evolutionary interplay between viruses and host. Table of Contents Abstract..............................................................................................................................2 Table of Contents............................................................................................................ 4 List of Tables.....................................................................................................................6 List of Figures.................................................................................................................. 7 List of Accompanying Materials....................................................................................9 Acknowledgement......................................................................................................... 11 Declaration......................................................................................................................12 Definitions....................................................................................................................... 13 Chapter 1 ........................................................................................................................ 17 General Introduction..................................................................................................17 Sum m ary................................................................................................................ 17 Brief history of retroviroiogy................................................................................ 17 Viral taxonomy.......................................................................................................23 Genomic organization of retroviruses............................................................... 26 Viral proteins and virion structure....................................................................... 28 Overview of the retroviral cycle...........................................................................33 Viral attachment and entry..............................................................................34 Reverse transcription....................................................................................... 35 Integration.......................................................................................................... 36 Expression of viral genes................................................................................ 38 Viral assembly................................................................................................... 42 Viral budding......................................................................................................44 M aturation.......................................................................................................... 46 Endogenous retroviruses.....................................................................................46 Biology of endogenous retroviruses..............................................................46 ERVs distribution...............................................................................................49 Interactions between exogenous and endogenous retroviruses............. 51 Endogenous retroviruses and disease......................................................... 53 Biological roles played by endogenous retroviruses...................................54 Jaagsiekte sheep retrovirus ....................................................................... 55 History............................................................................. 55 Ovine pulmonary adenocarcinoma (OPA)....................................................56 JSRV genomic organization and molecular pathogenesis....................... 57 Endogenous JSRVs......................................................................................... 61 Restriction factors and their role in intrinsic immunity against retroviruses 64 TRIM5 and Cyclophilin A ................................................................................. 65 AP O B EC s.......................................................................................................... 67 Zinc-finger antiviral protein (ZAP).................................................................. 69 enJS56A1........................................................................................................... 69 Concluding remarks..............................................................................................71 Chapter 2 .................................................................................................... 72 Materials and methods.............................................................................................72 Plasm ids................................................................................................................. 72 Cell cultures, transfections, viral preparations and cell lysates....................75 Western blot analysis............................................................................................76 Co-immunoprecipitation assays........................................................................
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