Prof. Martin Billeter

Measles virus (MV) has a nonsegmented RNA genome of negative polarity and thus belongs to the large viral order Mononegavirales, containing many important human and animal pathogens (1). The two most prominent families of this order are the Rhabdoviridae (eg. rabies virus, vesicular stomatitis virus (VSV) and many others, including also invertebrate and plant viruses) and the Paramyxoviridae (eg. MV, Sendai virus (SeV), parainfluenza viruses, mumps virus, respiratory syncytial virus and many others, all restricted to vertebrates as hosts). The basic features of the virion architecture, entry into host cells, replication and virion formation of all Mononegavirales, as far as elucidated on the molecular level, appear to be variations of a main strategy. Most studies on the biochemistry and molecular genetics of Mononegavirales have been carried out with VSV and SeV which both multiply to very high titers. However, our recent establishment of a system to rescue MV from reconstituted antigenomic cDNA and thus the possibility to apply reverse genetics to MV now provides a methodology to tackle questions either pertaining to Mononegavirales in general or to MV, a strictly human pathogen, in particular (2).

a) MV replication/transcription and related topics.
Several general aspects of Mononegavirales replication transcription, such as promoter functions, intergenic transcription stop/restart signals, nature of the tight protein association to the genomic RNA in replicating and transcribing RNPs can now be tackled. In addition, more specifically MV-related features which we have identified in the past (cotranscriptional RNA editing (3), hypermutations converting up to 50% of A residues to G in long MV genomic segments (4)) can now be analysed in mechanistic terms.

b) Pathogenic aspects of MV.
As a pathogen, MV is still important, causing the death of about one million children annually in developing countries; in addition, after the virtual disappearence of MV in industrialized countries in consequence of the general use of attenuated MV strains which are excellent live vaccines, usually providing life-long immunity against MV, in recent years small MV outbreaks have occurred also in the western hemisphere. Thus, the World Health Organization aims at the eradication of MV, which may require the development of at least updated attenuated MV vaccines, taking account of the wt MV evolution during three decades since the development of attenuated MV strains.
Two hallmarks of MV as a pathogen are the induction of pronounced general immunosuppression, favoring secondary infections (similar to the AIDS syndrome, but restricted in time), and its tendency to persist, causing in very rare cases the development of subacute sclerosing panencephalitis (SSPE). This is a fatal disease of the central nervous system which can develop many years after an acute MV infection (but not after vaccination with attenuated MV). We and others have cloned and sequenced a considerable number of MV variant genes from SSPE autopsy material and have found several characteristic mutational patterns affecting either all or many MVs causing SSPE (5). A full appreciation of the biological consequences of the mutations found in such SSPE MV variants as well as the dissection of the mechanism(s) underlying MV-induced immunosuppression is now feasible using the novel MV rescue system. These studies are carried out in collaboration with laboratories specialized in immune research.

c) Utilization of MV as a vector.
MV might be applicable for practical purposes. On one hand, we have developed MVs expressing additional proteins (CAT, green fluorescence protein (GFP), beta-galactosidase) and have monitored a remarkable genetic stability unprecedented in RNA virus vectors belonging to other families. This stability must be due to the very tight genomic RNP structure. In consideration of the excellent performance of attenuated MV vaccines and in view of the fact that massive use of this MV vaccine will be mandatory both in industrialized and in developing countries to reach the goal of MV eradication (currently estimated by the WHO to be achieved not sooner than within 15 years) it seems worthwhile to enrich the presently available MV vaccine strains with sequences encoding proteins of other pathogens to develop inexpensive multivalent vaccines for long term immune protection. It remains to be ascertained whether the MV dependent genetic stability of the presently utilized marker genes, monitored by serial transfers in cell culture, will hold true also for other coding sequences and viral propagation in animals or humans. In any event, strategies for expression of added coding regions other than those currently employed will be tested.
On the other hand it might be possible to use MV and other Mononegavirales as small nonintegrating RNA vectors for cytotoxic gene therapy to eliminate cancerous or infected cells. Our finding that the envelope protein coding sequences of MV can be completely substituted by that of VSV G glycoprotein to obtain reasonably viable chimeras provides an encouraging start in this direction.


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		Measles virus replication, pathogenesis, and use as a vector Martin A. Billeter (Professor Emeritus) Institut für Molekularbiologie Y55-K22 Winterthurerstrasse 190 8057 Zürich Schweiz phone: +41-1-63 53123 fax: +41-1-63 56864 billeter@molbio.unizh.ch e-mail: billeter [at] access.uzh.ch

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Research Measles virus (MV) has a nonsegmented RNA genome of negative polarity and thus belongs to the large viral order Mononegavirales, containing many important human and animal pathogens (1). The two most prominent families of this order are the Rhabdoviridae (eg. rabies virus, vesicular stomatitis virus (VSV) and many others, including also invertebrate and plant viruses) and the Paramyxoviridae (eg. MV, Sendai virus (SeV), parainfluenza viruses, mumps virus, respiratory syncytial virus and many others, all restricted to vertebrates as hosts). The basic features of the virion architecture, entry into host cells, replication and virion formation of all Mononegavirales, as far as elucidated on the molecular level, appear to be variations of a main strategy. Most studies on the biochemistry and molecular genetics of Mononegavirales have been carried out with VSV and SeV which both multiply to very high titers. However, our recent establishment of a system to rescue MV from reconstituted antigenomic cDNA and thus the possibility to apply reverse genetics to MV now provides a methodology to tackle questions either pertaining to Mononegavirales in general or to MV, a strictly human pathogen, in particular (2). a) MV replication/transcription and related topics. Several general aspects of Mononegavirales replication transcription, such as promoter functions, intergenic transcription stop/restart signals, nature of the tight protein association to the genomic RNA in replicating and transcribing RNPs can now be tackled. In addition, more specifically MV-related features which we have identified in the past (cotranscriptional RNA editing (3), hypermutations converting up to 50% of A residues to G in long MV genomic segments (4)) can now be analysed in mechanistic terms. b) Pathogenic aspects of MV. As a pathogen, MV is still important, causing the death of about one million children annually in developing countries; in addition, after the virtual disappearence of MV in industrialized countries in consequence of the general use of attenuated MV strains which are excellent live vaccines, usually providing life-long immunity against MV, in recent years small MV outbreaks have occurred also in the western hemisphere. Thus, the World Health Organization aims at the eradication of MV, which may require the development of at least updated attenuated MV vaccines, taking account of the wt MV evolution during three decades since the development of attenuated MV strains. Two hallmarks of MV as a pathogen are the induction of pronounced general immunosuppression, favoring secondary infections (similar to the AIDS syndrome, but restricted in time), and its tendency to persist, causing in very rare cases the development of subacute sclerosing panencephalitis (SSPE). This is a fatal disease of the central nervous system which can develop many years after an acute MV infection (but not after vaccination with attenuated MV). We and others have cloned and sequenced a considerable number of MV variant genes from SSPE autopsy material and have found several characteristic mutational patterns affecting either all or many MVs causing SSPE (5). A full appreciation of the biological consequences of the mutations found in such SSPE MV variants as well as the dissection of the mechanism(s) underlying MV-induced immunosuppression is now feasible using the novel MV rescue system. These studies are carried out in collaboration with laboratories specialized in immune research. c) Utilization of MV as a vector. MV might be applicable for practical purposes. On one hand, we have developed MVs expressing additional proteins (CAT, green fluorescence protein (GFP), beta-galactosidase) and have monitored a remarkable genetic stability unprecedented in RNA virus vectors belonging to other families. This stability must be due to the very tight genomic RNP structure. In consideration of the excellent performance of attenuated MV vaccines and in view of the fact that massive use of this MV vaccine will be mandatory both in industrialized and in developing countries to reach the goal of MV eradication (currently estimated by the WHO to be achieved not sooner than within 15 years) it seems worthwhile to enrich the presently available MV vaccine strains with sequences encoding proteins of other pathogens to develop inexpensive multivalent vaccines for long term immune protection. It remains to be ascertained whether the MV dependent genetic stability of the presently utilized marker genes, monitored by serial transfers in cell culture, will hold true also for other coding sequences and viral propagation in animals or humans. In any event, strategies for expression of added coding regions other than those currently employed will be tested. On the other hand it might be possible to use MV and other Mononegavirales as small nonintegrating RNA vectors for cytotoxic gene therapy to eliminate cancerous or infected cells. Our finding that the envelope protein coding sequences of MV can be completely substituted by that of VSV G glycoprotein to obtain reasonably viable chimeras provides an encouraging start in this direction. Review references ter Meulen, V. and Billeter M.A., ed. (1995). Measles Virus. Curr. Top. Microbiol. Immunol. vol 191; Springer GmbH. Radecke, F. and Billeter, M.A. (1997). Reverse genetics meets the nonsegmented negative-strand RNA viruses. Reviews in Medical Virology 7, 49-63. Bass, B.L., Weintraub, H., Cattaneo, R. amd Billeter, M.A. (1989). Biased Hypermutation of viral RNA genomes could be due to unwinding/modification of double-stranded RNA. Cell 56, 331. Cattaneo, R. and Billeter, M.A. (1991). Mutations and A/I hypermutations in measles virus persistent infections. In: Kingsbury, D. ed. The paramyxoviruses; Plenum Press, New York. Billeter, M.A., Cattaneo, R., Spielhofer, P, Kaelin, K., Huber, M., Schmid, A., Baczko, K. and ter Meulen, V. (1994). Generation and properties of measles virus mutations typically associated with subacute sclerosing panencephalitis. Annals of the New York Academy of Sciences, 724,. 367-377

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Publications 2001 Roscic-Mrkic, B., Schwendener, R.A., Odermatt, B., Zuniga, A., Pavlovic, J., Billeter, M.A., and Cattaneo, R. (2001). Roles of macrophages in measles virus infection of genetically modified mice. J. Virol. 75, 3343-3351. Abstract Wang, Z., Hangartner, L., Cornu, T. I., Martin, L. R., Zuniga, A., Billeter, M. A., and Naim, H. Y. (2001). Recombinant measles viruses expressing heterologous antigens of mumps and simian immunodeficiency viruses. Vaccine 19, 2329-2336. Abstract 2000 Naim, H., Y., Ehler, E., and Billeter, M. A. (2000). Measles virus matrix protein specifies apical virus release and glycoprotein sorting in epithelial cells. EMBO J. 19, 1-10. Abstract Patterson, J.B., Thomas, D., Lewicki, H., Billeter, M.A., and Oldstone, M.B.A. (2000). V and C proteins of measles virus function as virulence factors in vivo. Virology 267, 80-89. Abstract Maisner, A., Mrkic, B., Herrler, G., Moll, M., Billeter, M.A., Cattaneo, R., and Klenk, H.-D. (2000). Recombinant measles virus requiring an exogenous protease for activation of infectivity. J. Gen. Virol. 81, 441-449. Abstract Mrkic, B., Odermatt, B., Klein, M.A., Billeter, M.A., Pavlovic, J., and Cattaneo, R. (2000). Lymphatic dissemination and comparative pathology of recombinant measles viruses in genetically modified mice. J. Virol. 74, 1364-1372. Abstract 1999 Duprex, W.P., McQuaid, S., Hangartner, L., Billeter, M. A., and Rima, B. K. (1999). Observation of measles virus cell-to-cell spread in astrocytoma cells by using green fluorescent protein-expressing recombinant virus. J. Virol. 73, 9568-9575. Abstract Duprex, W.P., Duffy, I, McQuaid, S., Hamill, L., Cosby, S.L., Billeter, M.A., Schneider-Schaulies, J., ter Meulen, V., and Rima, B.K. (1999). The H gene of rodent brain-adapted measles virus confers neurovirulence to the Edmonston Vaccine strain. J. Virol. 73, 6916-6922. Abstract Singh, M., Cattaneo, R., and Billeter, M.A. (1999). A recombinant measles virus expressing hepatitis B virus surface antigen induces humoral immune responses in genetically modified mice. J. Virol. 73, 4823-4828. Abstract Howley, P.M., Lafont, B., Spehner, D., Kaelin, K., Billeter, M.A., and Drillien, R. (1999). A functional measles virus replication and transcription machinery encoded by the vaccinia virus genome. J. Virol. Meth. 79, 65-74. Abstract Escoffier, C., Manié, S., Vincent, S, Muller, C.P., Billeter, M.A. and Gerlier, D. (1999). Non-structural C protein is required for efficient measles virus replication in human peripheral blood cells. J. Virol. 73, 1695-1698. Abstract Singh, M., and Billeter, M.A. (1999). A recombinant measles virus expressing biologically active human interleukin-12. J. Gen. Virol. 80, 101-106. Abstract 1998 Tober, C., Seufert., M., Schneider, H., Billeter, M.A., Johnston, I.C.D., Niewiesk, S., ter Meulen, V., and Schneider-Schaulies, S. (1998). Expression of measles virus V protein is associated with transcriptional control and pathogenicity. J. Virol. 72, 8124-8132. Abstract Valsamakis, A., Schneider, H., Auwaerter, P.G., Kaneshima, H., Billeter, M.A., and Griffin, D.E. (1998). Recombinant measles viruses with mutations in the C, V, or F gene have altered growth phenotypes in vivo. J. Virol. 72, 7754-7761. Abstract Fehr, T., Naim, H.Y., Bachmann, M.F., Ochsenbein, A., Spielhofer, P., Bucher, E., Hengartner, H., Billeter, M.A., and Zinkernagel, R.M. (1998). T-cell independent IgM and enduring protective IgG antibodies induced by chimeric measles viruses. Nature Medicine 4, 945-948. Abstract Cathomen, T., Mrkic, B., Spehner, D., Drillien R., Naef, R., Pavlovic, J., Aguzzi, A., Billeter, M.A., and Cattaneo, R. (1998). A matrix-less measles virus is infectious and elicits extensive cell fusion: consequences for propagation in the brain. EMBO J. 17, 3899-3908. Abstract Spielhofer, P., Bächi, T., Fehr, T., Christiansen, G., Cattaneo, R., Kaelin, K., Billeter, M.A., and Naim, H.Y. (1998). Chimeric measles viruses with a foreign envelope. J. Virol. 72, 2150-2159. Abstract 1997 Radecke, F., and Billeter, M. A. (1997). Reverse genetics meets the non-segmented negative-strand RNA viruses. Rev. Med. Virol. 7, 49-63. Schneider, H., Kaelin, K. and Billeter, M.A. (1997). Recombinant measles viruses defective for RNA editing and V protein synthesis are viable in cultured cells.Virology 227, 314-322. Abstract Scheider, H., Spielhofer, P., Kaelin, K., Dötsch, C., Radecke, F., Sutter, G. and Billeter, M.A. (1997). Rescue of measles virus using a replication-deficient vaccinia-T7 vector. J. Virol. Methods 64, 57-64. Abstract 1996 Schlender, J., Schnorr, J.-J., Spielhofer, P., Cathomen, T., Cattaneo, R., Billeter, M.A., ter Meulen, V., and Schneider-Schaulies, S. (1996). Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro. Proc. Natl. Acad. Sci. USA 93, 13194-13199. Abstract Bankamp, B., Horikami, S.M., Thompson, P.D., Huber, M., Billeter, M.A. and Moyer, S.A. (1996). Domains of the measles virus N protein required for binding to P protein and self-assembly. Virology 216, 272-277. Abstract Radecke, F. and Billeter, M.A. (1996). The nonstructural C protein is not essential for multiplication of Edmonston B strain measles virus in cultured cells. Virology 217, 418-421. Abstract 1995 Radecke, F., Spielhofer, P., Schneider, H., Kaelin, K., Huber, M., Dötsch, C., Christiansen, G. and Billeter, M. A. (1995). Rescue of measles viruses from cloned DNA. EMBO J. 14, 5773-5784. Abstract Sidhu, M.S., Chan, J., Kaelin, K., Spielhofer, P., Radecke, F., Schneider, H., Masurekar, M., Dowling, P.C., Billeter, M.A. and Udem, S.A. (1995). Rescue of synthetic measles virus minireplicons: measles genomic termini direct efficient expression and propagation of a reporter gene. Virology 208, 800-807. Abstract Komase, K., Rima, B.K., Pardowitz, I., Kunz, C., Billeter, M.A., ter Meulen, V., Baczko, K., (1995). A comparison of the nucleotide sequence of the measles virus L genes derived from wil-type viruses and SSPE brain tissues. Virology 208, 795-799. Abstract
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previous IMB work groups

Measles virus replication, pathogenesis, and use as a vector

Martin A. Billeter (Professor Emeritus)

Research

Review references

Publications

2001

2000

1999

1998

1997

1996

1995

previous IMB
work groups

Martin A. Billeter
(Professor Emeritus)