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Inhibition of Non-Primate Lentiviruses by Apobec3 Cytidine Deaminase

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Inhibition of Non-Primate Lentiviruses by Apobec3 Cytidine Deaminase INHIBITION OF NON-PRIMATE LENTIVIRUSES BY APOBEC3 CYTIDINE DEAMINASE Jörg Zielonka Freiheit ist immer Freiheit der Andersdenkenden Rosa Luxemburg INHIBITION OF NON-PRIMATE LENTIVIRUSES BY APOBEC3 CYTIDINE DEAMINASE vom Fachbereich Biologie der Technischen Universität Darmstadt zur Erlangung des akademischen Grades eines Doctor rerum naturalium genehmigte Dissertation von Diplom Biologe Jörg Zielonka aus Gardelegen Berichterstatter: Prof. Dr. H. Ulrich Göringer Mitberichterstatter: Prof. Dr. Gerhard Thiel Tag der Einreichung: 30.09.2010 Tag der mündlichen Prüfung: 18.01.2011 Darmstadt 2011 D17 Die vorliegende Arbeit wurde in der Arbeitsgruppe von Herrn Prof. Dr. Carsten Münk in der Klinik für Gastroenterologie, Hepatologie und Infektiologie an der Heinrich-Heine-Universität Düsseldorf angefertigt. Teile dieser Arbeit gehen in folgende Veröffentlichungen ein: Münk, C., T. Beck, J. Zielonka, A. Hotz-Wagenblatt, S. Chareza, M. Battenberg, J. Thielebein, K. Cichutek, I. G. Bravo, S. J. O'Brien, M. Löchelt, and N. Yuhki. 2008. Functions, structure, and read- through alternative splicing of feline APOBEC3 genes. Genome Biol 9:R48. Münk, C., J. Zielonka, H. Constabel, B. P. Kloke, B. Rengstl, M. Battenberg, F. Bonci, M. Pistello, M. Löchelt, and K. Cichutek. 2007. Multiple restrictions of human immunodeficiency virus type 1 in feline cells. J Virol 81:7048-60. Zielonka, J., I. G. Bravo, D. Marino, E. Conrad, M. Perkovic, M. Battenberg, K. Cichutek, and C. Münk. 2009. Restriction of equine infectious anemia virus by equine APOBEC3 cytidine deaminases. J Virol 83:7547-59. Zielonka, J., D. Marino, H. Hofmann, N. Yuhki, M. Löchelt, and C. Münk. Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids. J Virol 84:7312-24. 6/CHAPTER 1 General Introduction 14/CHAPTER 2 Multiple Restrictions of Human Immunodeficiency Virus Type 1 in Feline Cells 27/CHAPTER 3 Functions, Structure, and Read-through Alternative Splicing of Feline APOBEC3 Genes 46/CHAPTER 4 Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases 60/CHAPTER 5 Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids 73/SUMMARY 74/ZUSAMMENFASSUNG CHAPTER 1 General Introduction RETROVIRUSES of the plus-strand DNA. The polypurine tract is followed by another unique sequence termed U3. The U3 region contains Retroviruses are RNA viruses, characterized by two essential one of the attachment sites and a number of key cis-acting steps in their replication: reverse transcription of the single- elements for viral gene expression. The 3’ copy of the R region, stranded RNA genome into double-stranded DNA and its which is followed by the poly (A) tail, is located downstream to integration into the host chromosomal DNA. the U3 region. These membrane-coated viruses carry two identical copies of The retroviral replication cycle is a multi-step process (FIG. a single-stranded RNA genome. The retroviral RNA molecules 2). The major steps are receptor binding and entry, uncoating, form a dimer stabilized by the dimer linkage structure (DLS) reverse transcription, transport of viral DNA into the nucleus, located near the 5’-end of each molecule. All retroviral genomes integration into chromosomal DNA, transcription of proviral consist of three major genes: gag, pol and env (FIG. 1). The DNA, splicing of primary transcripts, export of mRNAs to the genomic RNA is capped at the 5’-end by an m7G5’ppp5’Gmp cytoplasm, translation and post-translational modification, structure, whereas the 3’-end contains a poly (A) tail. At both assembly, release, and maturation. The virus binds to host cell ends, immediately after the cap at the 5’ end and upstream to the receptors via its receptor binding site (RBS), which is located poly (A) tail, there are short identical repeated sequences (R). in the surface glycoprotein. Binding causes conformational Downstream to the 5’-R lies a unique non-repeated sequence, changes in both the receptor and viral envelope leading to the termed U5, which includes one of the attachment (att) sites fusion of virus and cell membranes, internalization of the viral required for proviral integration. The U5 region is followed by core and uncoating. Reverse transcription takes place in the the primer binding site (PBS), the site of initiation of reverse cytoplasm in a reverse transcription complex which includes transcription at which a host tRNA is bound. Encapsidation of the viral RNA, the enzymes (reverse transcriptase, ribonuclease the viral genomic RNA into the viral particle requires a specific H, and integrase), and the nucleocapsid protein. The viral sequence, called ψ (psi) which is located downstream to the dsDNA that results from reverse transcription is transported as primer binding site. The bulk of sequences that follow are genes a pre-integration complex to the nucleus. The integrase cuts the encoding viral proteins. They are organized in three major DNA of a host chromosome and integrates the viral DNA into regions: gag (group-specific antigen), pol (polymerase), and env the gap. The integrated provirus replicates synchronously with (envelope). The gag gene encodes matrix (MA), capsid (CA) cellular DNA and each of the daughter cells carries a copy of and nucleocapsid (NC). The pol gene encodes the enzymes: the integrated viral DNA. The cellular RNA polymerase II starts reverse transcriptase (RT), ribonuclease H (RH), and integrase transcription at the U3-R junction in the 5’ long terminal repeat (IN). The env gene encodes two envelope proteins, the surface (LTR) and continues to a point located at the R-U5 junction in glycoprotein (SU) and the transmembrane glycoprotein (TM). the 3’LTR. Each full-length transcript is capped and carries a At the 3’ end of the genomic RNA, downstream of the env gene poly (A) tail. RNA transcripts are divided into two populations: lies a short polypurine tract (PPT), which is the initiation-site spliced and unspliced. Unspliced transcripts serve as genomic FIG. 1. Retroviral genome organization. The genome organization of a typical retroviral provirus is shown in comparison to the genome organizations of EIAV (Equine infectious anemia virus) and FIV (Feline immunodeficiency virus). FIG. 2. Gag-Pol by the viral protease. After Gag cleavage the matrix, the capsid and the nucleocapsid proteins are released, while the cleavage of Pol forms the viral enzymes. LENTIVIRUSES The genus Lentivirus of the Retroviridae family is characterized by its morphology, accessory genes, which are not present in other retroviral genomes, and by a biphasic course of viral gene expression. Six subgroups of lentiviruses (primate, feline, ovine, bovine, equine, and lagomorph lentivirus) were identified, reflecting the mammalian hosts with which they are associated. In 2007 the last group of lagomorpha lentiviruses was discovered in the European rabbit (Oryctolagus cuniculus) (45). It was the first characterized endogenous lentivirus, which was termed rabbit endogenous lentivirus type K (RELIK). This virus is >7 million years old and thus provide evidence for an ancient origin of the lentiviruses. The lentiviruses are naturally restricted in their host range, but natural cross-species infections have been detected for SIV (Simian immunodeficiency virus) in different monkey lineages FIG. 2. Scheme of retroviral replication cycle. 1, attachment to (32, 39). In addition, experimental infections of Baboons with the cell surface receptor; 2, internalization; 3, core disassembly HIV-2 (Human immunodeficiency virus-2) and chimpanzees and release of viral RNA; 4, reverse transcription into genomic with HIV-1 were reported (57, 58, 72), but transmissions of SIV DNA; 5, transport into the nucleus; 6, integration of genomic and HIV to non-primates were unsuccessful. DNA in the cellular chromosomal DNA; 7, synthesis of RNA All lentiviruses have the ability to replicate in macrophages. transcripts and transport of newly synthesized genomic RNAs to HIV and SIV also infect CD4+ lymphocytes. Primate lentiviruses the cytoplasm; 8, transcription of mRNA encoding viral proteins use a receptor (CD4) and a chemokine co-receptor (mainly and transport of these transcripts in the cytoplasm; 9, translation CCR5 and CXCR4) for entering these target cells. CXCR4 is also of viral proteins; 10, transport of structural viral proteins and used by the non-primate lentivirus FIV (Feline immunodeficiency genomic RNAs to the sites of assembly; 11, assembly and virus) as entry co-receptor (22, 75, 94, 108). budding of virions; 12, mature virions. Figure taken from (106). In addition to the gag, pol, and env structural genes present in all retroviruses, the majority of lentiviruses have additional genes like tat (transactivator of transcription) and rev (regulatory virus factor). Tat is essential for the replication of HIV, SIV and EIAV (Equine infectious anemia virus) as a general RNA, or become translated into Gag, Gag-Pro, and Gag-Pro- activator of transcription. All three lentiviruses have long Pol precursor polyproteins. The precursor proteins encoded by terminal repeats with low basal activity that is strongly induced the env gene are translated from spliced mRNAs. The envelope by their respective Tat proteins. Rev protein regulates the export proteins are cleaved by a cellular protease into surface and of unspliced and single spliced viral RNA containing a Rev transmembrane molecules, glycosylated and transported from response element (RRE) from
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