D型肝炎病毒 (HDV) 為唯一以細胞RNA聚合脢 (polymerase) 催化RNA基因體複製之動物病毒，且複製過程中也有RNA 重組的現象發生。本文以template switch機制為出發點探討可能影響HDV RNA重組的因素－RNA二級結構及接收模板 (acceptor template) 的濃度。HDV RNA雖為桿狀不分枝結構，但在複製過程中桿狀結構有機會在RNA聚合酶附近鬆解而形成二級結構，進而造成RNA 聚合酶與新合成之RNA一起掉落並跳至接收模板。首先，我分析重組頻率特別高的區域附近可能形成之二級結構，找到一個可能影響重組率的stem-loop，將其單點突變，增加stem-loop的穩定度，發現此區域的重組率提升;再用雙點突變降低此處之穩定度，發現重組分佈回復如野生型，證實重組頻率會受RNA二級結構的影響；在分析過程中觀察到另ㄧ有趣之現象，即HDV RNA重組存在aberrant homologous recombination。再者，我利用不同比例的兩株HDV分析接收模板 (acceptor template) 濃度的影響，從初步結果看來，重組的產生多來自於基因股合成方向，且接收模板的濃度也是影響重組發生頻率高低的重要因素。這些結果皆支持HDV RNA重組是經由template switch的機制進行的，如此不僅能幫助我們更了解HDV重組的分子機制，也可擴展寄主RNA聚合酶功能的多樣性。

Hepatitis delta virus (HDV) is the only animal virus that replicated it’s RNA genomes by host RNA polymerase. RNA recombination has been found in a large number of RNA viruses including HDV. Although the molecular mechanism of RNA recombination is not fully understood, the replication-dependent template-switching mechanism has been proposed to contribute to most of the RNA recombination events. RNA secondary structure and the concentration of acceptor template have been suggested to determine recombination frequency. The aim of my thesis is to investigate the role of these factors in HDV RNA recombination. Although the HDV RNA is a rod-like structure, it could undergo dynamic conformational changes around the polymerase binding site during genome replication. These changes may contribute to the formation of a local RNA secondary structure which induce polymerase pausing and template switching. It has been published that nt 1159-1207 on the HDV genome is a RNA recombination hot spot. Interestingly, I found a G-C rich stem-loop structure at the 5’-end of this hot spot. To investigate the potential role of this structure in HDV RNA recombination, point mutations that affect the stability of the stem-loop were constructed. The results indicated that the recombination frequency around the stem-loop was increased significantly when a point mutation was introduced to strengthen the stem-loop. In contrast, this effect was reversed when a compensatory mutation of this point mutation was constructed to reduce the stem-loop stability. Further analyses of the recombination junctions of the recombinants, aberrant homologous recombination was observed in HDV. To investigate the role of the acceptor concentration in recombination frequency, I examined the recombination patterns between two HDV genotypes with different ratios. The results suggested that HDV recombination occurs mainly during genomic RNA synthesis, and the acceptor concentration is an important factor determining the recombination frequency. Taken together, HDV RNA recombination could be carried out by template- switching mechanism. These results not only contribute to the elucidation of, but also expand the capacity of host RNA polymerase.

指導教授推薦書…………………………………………………………… i
口試委員會審定書………………………………………………………… ii
授權書……………………………………………………………………… iii
誌謝………………………………………………………………………… iv
中文摘要…………………………………………………………………… v
英文摘要…………………………………………………………………… vi
目錄………………………………………………………………………… vii
圖表目錄………………………………………………………...……… viii
第一章 緒論……………………………………………………………… 1
第二章 材料與方法……………………………………………………… 23
第三章 實驗結果………………………………………………………… 33
第四章 討論……………………………………………………………… 48
參考文獻…………………………………………………………………… 59
圖表………………………………………………………………………… 72
附錄………………………………………………………………………… 102

Anisimova, M. and Yang, Z. (2004) Molecular evolution of the hepatitis delta virus antigen gene: recombination or positive selection? J Mol Evol, 59, 815-826.
Banner, L.R. and Lai, M.M. (1991) Random nature of coronavirus RNA recombination in the absence of selection pressure. Virology, 185, 441-445.
Baric, R.S., Shieh, C.K., Stohlman, S.A. and Lai, M.M. (1987) Analysis of intracellular small RNAs of mouse hepatitis virus: evidence for discontinuous transcription. Virology, 156, 342-354.
Beard, M.R., MacNaughton, T.B. and Gowans, E.J. (1996) Identification and characterization of a hepatitis delta virus RNA transcriptional promoter. J Virol, 70, 4986-4995.
Bergmann, K.F. and Gerin, J.L. (1986) Antigens of hepatitis delta virus in the liver and serum of humans and animals. J Infect Dis, 154, 702-706.
Bichko, V., Barik, S. and Taylor, J. (1997) Phosphorylation of the hepatitis delta virus antigens. J Virol, 71, 512-518.
Bonino, F., Heermann, K.H., Rizzetto, M. and Gerlich, W.H. (1986) Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J Virol, 58, 945-950.
Braman, J., Papworth, C. and Greener, A. (1996) Site-directed mutagenesis using double-stranded plasmid DNA templates. Methods Mol Biol, 57, 31-44.
Branch, A.D., Benenfeld, B.J., Baroudy, B.M., Wells, F.V., Gerin, J.L. and Robertson, H.D. (1989) An ultraviolet-sensitive RNA structural element in a viroid-like domain of the hepatitis delta virus. Science, 243, 649-652.
Branch, A.D. and Robertson, H.D. (1984) A replication cycle for viroids and other small infectious RNA's. Science, 223, 450-455.
Brazas, R. and Ganem, D. (1996) A cellular homolog of hepatitis delta antigen: implications for viral replication and evolution. Science, 274, 90-94.
Bujarski, J.J. and Dzianott, A.M. (1991) Generation and analysis of nonhomologous RNA-RNA recombinants in brome mosaic virus: sequence complementarities at crossover sites. J Virol, 65, 4153-4159.
Carpenter, C.D., Oh, J.W., Zhang, C. and Simon, A.E. (1995) Involvement of a stem-loop structure in the location of junction sites in viral RNA recombination. J Mol Biol, 245, 608-622.
Cascone, P.J., Haydar, T.F. and Simon, A.E. (1993) Sequences and structures required for recombination between virus-associated RNAs. Science, 260, 801-805.
Casey, J.L., Brown, T.L., Colan, E.J., Wignall, F.S. and Gerin, J.L. (1993) A genotype of hepatitis D virus that occurs in northern South America. Proc Nati Acad Sci U S A, 90, 9016-9020.
Casey, J.L., Niro, G.A., Engle, R.E., Vega, A., Gomez, H., McCarthy, M., Watts, D.M., Hyams, K.C. and Gerin, J.L. (1996) Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. Journal Infect Dis, 174, 920-926.
Chang, J. and Taylor, J. (2002) In vivo RNA-directed transcription, with template switching, by a mammalian RNA polymerase. Embo J, 21, 157-164.
Chang, M.F., Baker, S.C., Soe, L.H., Kamahora, T., Keck, J.G., Makino, S., Govindarajan, S. and Lai, M.M. (1988) Human hepatitis delta antigen is a nuclear phosphoprotein with RNA-binding activity. J Virol, 62, 2403-2410.
Chang, M.F., Chang, S.C., Chang, C.I., Wu, K. and Kang, H.Y. (1992) Nuclear localization signals, but not putative leucine zipper motifs, are essential for nuclear transport of hepatitis delta antigen. J Virol, 66, 6019-6027.
Chang, M.F., Sun, C.Y., Chen, C.J. and Chang, S.C. (1993) Functional motifs of delta antigen essential for RNA binding and replication of hepatitis delta virus. J Virol, 67, 2529-2536.
Chao, M., Hsieh, S.Y. and Taylor, J. (1990a) Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J Virol, 64, 5066-5069.
Chao, Y.C., Chang, M.F., Gust, I. and Lai, M.M. (1990b) Sequence conservation and divergence of hepatitis delta virus RNA. Virology, 178, 384-392.
Chen, P.J., Kalpana, G., Goldberg, J., Mason, W., Werner, B., Gerin, J. and Taylor, J. (1986) Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci U S A, 83, 8774-8778.
Chetverin, A.B., Chetverina, H.V., Demidenko, A.A. and Ugarov, V.I. (1997) Nonhomologous RNA recombination in a cell-free system: evidence for a transesterification mechanism guided by secondary structure. Cell, 88, 503-513.
Chou, H.C., Hsieh, T.Y., Sheu, G.T. and Lai, M.M. (1998) Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA. J Virol, 72, 3684-3690.
Copper, P.D., Steiner-Pryor, A., Scotti, P.D. and Delong, D. (1974) On the nature of poliovirus genetic recombinants. J Gen Virol, 23, 41-49.
de Bruin, W., Leenders, W., Kos, T. and Yap, S.H. (1994) In vitro binding properties of the hepatitis delta antigens to the hepatitis B virus envelope proteins: potential significance for the formation of delta particles. Virus Res, 31, 27-37.
Fields, B.N. (1981) Genetics of Reovirus. Curr Top Microbiol Immunol, 91, 1-24.
Fu, T.B. and Taylor, J. (1993) The RNAs of hepatitis delta virus are copied by RNA polymerase II in nuclear homogenates. J Virol, 67, 6965-6972.
Giachetti, C. and Semler, B.L. (1991) Role of a viral membrane polypeptide in strand-specific initiation of poliovirus RNA synthesis.[erratum appears in J Virol 1991 Jul;65(7):3972]. J Virol, 65, 2647-2654.
Gmyl, A.P., Belousov, E.V., Maslova, S.V., Khitrina, E.V., Chetverin, A.B. and Agol, V.I. (1999) Nonreplicative RNA recombination in poliovirus. J Virol, 73, 8958-8965.
Govindarajan, S., Chin, K.P., Redeker, A.G. and Peters, R.L. (1984) Fulminant B viral hepatitis: role of delta agent. Gastroenterology, 86, 1417-1420.
Gudima, S., Chang, J., Moraleda, G., Azvolinsky, A. and Taylor, J. (2002) Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA. J Virol, 76, 3709-3719.
Gudima, S.O., Chang, J. and Taylor, J.M. (2005) Reconstitution in cultured cells of replicating HDV RNA from pairs of less than full-length RNAs. Rna, 11, 90-98.
Hadler, S.C., De Monzon, M., Ponzetto, A., Anzola, E., Rivero, D., Mondolfi, A., Bracho, A., Francis, D.P., Gerber, M.A., Thung, S. and et al. (1984) Delta virus infection and severe hepatitis. An epidemic in the Yucpa Indians of Venezuela. Ann Intern Med, 100, 339-344.
Haseltine, W.A., Kleid, D.G., Panet, A., Rothenberg, E. and Baltimore, D. (1976) Ordered transcription of RNA tumor virus genomes. J Mol Biol, 106, 109-131.
Hirst, G.K. (1962) Genetic recombination with Newcastle disease virus, polioviruses, and influenza. Cold Spring Harb Symp Quant Biol, 27, 303-309.
Holland, J., Spindler, K., Horodyski, F., Grabau, E., Nichol, S. and VandePol, S. (1982) Rapid evolution of RNA genomes. Science, 215, 1577-1585.
Hoofnagle, J.H. (1989) Type D (delta) hepatitis.[see comment][erratum appears in JAMA 1989 Jun 23-30;261(24):3552]. JAMA, 261, 1321-1325.
Hsieh, S.Y. and Taylor, J. (1991) Regulation of polyadenylation of hepatitis delta virus antigenomic RNA. J Virol, 65, 6438-6446.
Huang, W.H., Yung, B.Y., Syu, W.J. and Lee, Y.H. (2001) The nucleolar phosphoprotein B23 interacts with hepatitis delta antigens and modulates the hepatitis delta virus RNA replication. J Biol Chem, 276, 25166-25175.
Huang, Z.S. and Wu, H.N. (1998) Identification and characterization of the RNA chaperone activity of hepatitis delta antigen peptides. J Biol Chem, 273, 26455-26461.
Hwang, S.B., Lee, C.Z. and Lai, M.M. (1992) Hepatitis delta antigen expressed by recombinant baculoviruses: comparison of biochemical properties and post-translational modifications between the large and small forms. Virology, 190, 413-422.
Imazeki, F., Omata, M. and Ohto, M. (1991) Complete nucleotide sequence of hepatitis delta virus RNA in Japan. Nucleic Acids Res, 19, 5439.
Ivaniushina, V., Radjef, N., Alexeeva, M., Gault, E., Semenov, S., Salhi, M., Kiselev, O. and Deny, P. (2001) Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia. J Gen Virol, 82, 2709-2718.
Jayan, G.C. and Casey, J.L. (2002) Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression. J Virol, 76, 12399-12404.
Jeng, K.S., Su, P.Y. and Lai, M.M. (1996) Hepatitis delta antigens enhance the ribozyme activities of hepatitis delta virus RNA in vivo. J Virol, 70, 4205-4209.
Kirkegaard, K. and Baltimore, D. (1986) The mechanism of RNA recombination in poliovirus. Cell, 47, 433-443.
Kuo, M.Y., Chao, M. and Taylor, J. (1989) Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol, 63, 1945-1950.
Kuo, M.Y., Goldberg, J., Coates, L., Mason, W., Gerin, J. and Taylor, J. (1988) Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol, 62, 1855-1861.
Lai, M.M. (1992) RNA recombination in animal and plant viruses. Microbiol Rev, 56, 61-79.
Lai, M.M. (1995) The molecular biology of hepatitis delta virus. Annu Rev Biochem, 64, 259-286.
Lai, M.M. (2005) RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J Virol, 79, 7951-7958.
Lang, W.H. and Reeder, R.H. (1995) Transcription termination of RNA polymerase I due to a T-rich element interacting with Reb1p. Proc Natl Acad Sci U S A, 92, 9781-9785.
Lazinski, D.W. and Taylor, J.M. (1994) Expression of hepatitis delta virus RNA deletions: cis and trans requirements for self-cleavage, ligation, and RNA packaging. J Virol, 68, 2879-2888.
Le Gal, F., Gault, E., Ripault, M.P., Serpaggi, J., Trinchet, J.C., Gordien, E. and Deny, P. (2006) Eighth major clade for hepatitis delta virus. Emerg Infect Dis, 12, 1447-1450.
Ledinko, N. (1963) Genetic recombination with poliovirus type 1. Studies of crosses between a normal horse serum-resistant mutant and several guanidine-resistant mutants of the same strain. Virology, 20, 107-119.
Lee, C.M., Changchien, C.S., Chung, J.C. and Liaw, Y.F. (1996) Characterization of a new genotype II hepatitis delta virus from Taiwan. J Med Virol, 49, 145-154.
Lee, C.Z., Lin, J.H., Chao, M., McKnight, K. and Lai, M.M. (1993) RNA-binding activity of hepatitis delta antigen involves two arginine-rich motifs and is required for hepatitis delta virus RNA replication. J Virol, 67, 2221-2227.
Li, Y.J., Macnaughton, T., Gao, L. and Lai, M.M. (2006) RNA-templated replication of hepatitis delta virus: genomic and antigenomic RNAs associate with different nuclear bodies. J Virol, 80, 6478-6486.
Li, Y.J., Stallcup, M.R. and Lai, M.M. (2004) Hepatitis delta virus antigen is methylated at arginine residues, and methylation regulates subcellular localization and RNA replication. J Virol, 78, 13325-13334.
Macdonald, L.E., Zhou, Y. and McAllister, W.T. (1993) Termination and slippage by bacteriophage T7 RNA polymerase. J Mol Biol, 232, 1030-1047.
MacNaughton, T.B., Gowans, E.J., McNamara, S.P. and Burrell, C.J. (1991) Hepatitis delta antigen is necessary for access of hepatitis delta virus RNA to the cell transcriptional machinery but is not part of the transcriptional complex. Virology, 184, 387-390.
Macnaughton, T.B. and Lai, M.M. (2002) Genomic but not antigenomic hepatitis delta virus RNA is preferentially exported from the nucleus immediately after synthesis and processing. J Virol, 76, 3928-3935.
Macnaughton, T.B., Shi, S.T., Modahl, L.E. and Lai, M.M. (2002) Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J Virol, 76, 3920-3927.
Macnaughton, T.B., Wang, Y.J. and Lai, M.M. (1993) Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J Virol, 67, 2228-2234.
Makino, S., Chang, M.F., Shieh, C.K., Kamahora, T., Vannier, D.M., Govindarajan, S. and Lai, M.M. (1987) Molecular cloning and sequencing of a human hepatitis delta (delta) virus RNA. Nature, 329, 343-346.
Modahl, L.E. and Lai, M.M. (1998) Transcription of hepatitis delta antigen mRNA continues throughout hepatitis delta virus (HDV) replication: a new model of HDV RNA transcription and replication. J Virol, 72, 5449-5456.
Modahl, L.E. and Lai, M.M. (2000) The large delta antigen of hepatitis delta virus potently inhibits genomic but not antigenomic RNA synthesis: a mechanism enabling initiation of viral replication. J Virol, 74, 7375-7380.
Modahl, L.E., Macnaughton, T.B., Zhu, N., Johnson, D.L. and Lai, M.M. (2000) RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol Cell Biol, 20, 6030-6039.
Mu, J.J., Chen, D.S. and Chen, P.J. (2001) The conserved serine 177 in the delta antigen of hepatitis delta virus is one putative phosphorylation site and is required for efficient viral RNA replication. J Virol, 75, 9087-9095.
Nagy, P.D. and Bujarski, J.J. (1995) Efficient system of homologous RNA recombination in brome mosaic virus: sequence and structure requirements and accuracy of crossovers. J Virol, 69, 131-140.
Nagy, P.D. and Simon, A.E. (1997) New insights into the mechanisms of RNA recombination. Virology, 235, 1-9.
Nie, X., Chang, J. and Taylor, J.M. (2004) Alternative processing of hepatitis delta virus antigenomic RNA transcripts. J Virol, 78, 4517-4524.
Novak, J.E. and Kirkegaard, K. (1991) Improved method for detecting poliovirus negative strands used to demonstrate specificity of positive-strand encapsidation and the ratio of positive to negative strands in infected cells. J Virol, 65, 3384-3387.
Palese, P. (1977) The genes of influenza virus. Cell, 10, 1-10.
Radjef, N., Gordien, E., Ivaniushina, V., Gault, E., Anais, P., Drugan, T., Trinchet, J.C., Roulot, D., Tamby, M., Milinkovitch, M.C. and Deny, P. (2004) Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades. J Virol, 78, 2537-2544.
Rizzetto, M., Hoyer, B., Canese, M.G., Shih, J.W., Purcell, R.H. and Gerin, J.L. (1980) delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. Proc Nati Acad Sci U S A, 77, 6124-6128.
Ryu, W.S., Netter, H.J., Bayer, M. and Taylor, J. (1993) Ribonucleoprotein complexes of hepatitis delta virus. J Virol, 67, 3281-3287.
Shakil, A.O., Hadziyannis, S., Hoofnagle, J.H., Di Bisceglie, A.M., Gerin, J.L. and Casey, J.L. (1997) Geographic distribution and genetic variability of hepatitis delta virus genotype I. Virology, 234, 160-167.
Sheu, G.T. and Lai, M.M. (2000) Recombinant hepatitis delta antigen from E. coli promotes hepatitis delta virus RNA replication only from the genomic strand but not the antigenomic strand. Virology, 278, 578-586.
Strauss, J.H. and Strauss, E.G. (1988) Evolution of RNA viruses. Annu Rev Microbiol, 42, 657-683.
Tavanez, J.P., Cunha, C., Silva, M.C., David, E., Monjardino, J. and Carmo-Fonseca, M. (2002) Hepatitis delta virus ribonucleoproteins shuttle between the nucleus and the cytoplasm. Rna, 8, 637-646.
Taylor, J.M. (1999) Human hepatitis delta virus: an agent with similarities to certain satellite RNAs of plants. Curr Top Microbiol Immunol, 239, 107-122.
Tolskaya, E.A., Romanova, L.I., Blinov, V.M., Viktorova, E.G., Sinyakov, A.N., Kolesnikova, M.S. and Agol, V.I. (1987) Studies on the recombination between RNA genomes of poliovirus: the primary structure and nonrandom distribution of crossover regions in the genomes of intertypic poliovirus recombinants. Virology, 161, 54-61.
Wang, J.G. and Lemon, S.M. (1993) Hepatitis delta virus antigen forms dimers and multimeric complexes in vivo. J Virol, 67, 446-454.
Wang, K.S., Choo, Q.L., Weiner, A.J., Ou, J.H., Najarian, R.C., Thayer, R.M., Mullenbach, G.T., Denniston, K.J., Gerin, J.L. and Houghton, M. (1986) Structure, sequence and expression of the hepatitis delta (delta) viral genome.[erratum appears in Nature 1987 Jul 30-Aug 5;328(6129):456]. Nature, 323, 508-514.
Wang, T.C. and Chao, M. (2005) RNA recombination of hepatitis delta virus in natural mixed-genotype infection and transfected cultured cells. J Virol, 79, 2221-2229.
Watanabe, H., Nagayama, K., Enomoto, N., Chinzei, R., Yamashiro, T., Izumi, N., Yatsuhashi, H., Nakano, T., Robertson, B.H., Nakasone, H., Sakugawa, H. and Watanabe, M. (2003) Chronic hepatitis delta virus infection with genotype IIb variant is correlated with progressive liver disease. J Gen Virol, 84, 3275-3289.
White, K.A. and Morris, T.J. (1995) RNA determinants of junction site selection in RNA virus recombinants and defective interfering RNAs. Rna, 1, 1029-1040.
Wilson, K.S. and von Hippel, P.H. (1995) Transcription termination at intrinsic terminators: the role of the RNA hairpin. Proc Natl Acad Sci U S A, 92, 8793-8797.
Wilson, V., Taylor, P. and Desselberger, U. (1988) Crossover regions in foot-and-mouth disease virus (FMDV) recombinants correspond to regions of high local secondary structure. Arch Virol, 102, 131-139.
Wu, H.N. and Lai, M.M. (1989) Reversible cleavage and ligation of hepatitis delta virus RNA.[erratum appears in Science 1989 Mar 17;243(4897):1420]. Science, 243, 652-654.
Wu, J.C., Chen, C.M., Sheen, I.J., Lee, S.D., Tzeng, H.M. and Choo, K.B. (1995) Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome. Hepatology, 22, 1656-1660.
Wu, J.C., Chiang, T.Y. and Sheen, I.J. (1998) Characterization and phylogenetic analysis of a novel hepatitis D virus strain discovered by restriction fragment length polymorphism analysis. J Gen Virol, 79 ( Pt 5), 1105-1113.
Wu, J.C., Chiang, T.Y., Shiue, W.K., Wang, S.Y., Sheen, I.J., Huang, Y.H. and Syu, W.J. (1999) Recombination of hepatitis D virus RNA sequences and its implications. Mol Biol Evol, 16, 1622-1632.
Xia, Y.P. and Lai, M.M. (1992) Oligomerization of hepatitis delta antigen is required for both the trans-activating and trans-dominant inhibitory activities of the delta antigen. J Virol, 66, 6641-6648.
Xia, Y.P., Yeh, C.T., Ou, J.H. and Lai, M.M. (1992) Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex. J Virol, 66, 914-921.
Yeh, T.S., Lo, S.J., Chen, P.J. and Lee, Y.H. (1996) Casein kinase II and protein kinase C modulate hepatitis delta virus RNA replication but not empty viral particle assembly. J Virol, 70, 6190-6198.
Zhang, Y.Y., Tsega, E. and Hansson, B.G. (1996) Phylogenetic analysis of hepatitis D viruses indicating a new genotype I subgroup among African isolates. J Clin Microbiol, 34, 3023-3030.