Recombinant measles viruses with mutations in the C, V, or F gene have altered growth phenotypes in vivo

Alexandra Valsamakis, Henriette Schneider, Paul G Auwaerter, Hideto Kaneshima, Martin A. Billeter, Diane Griffin

Research output: Contribution to journalArticle

Abstract

An understanding of the determinants of measles virus (MV) virulence has been hampered by the lack of an experimental model of infection. We have previously demonstrated that virulence phenotypes in human infections are faithfully reproduced by infection of human thymus/liver (thy/liv) implants engrafted into SCID mice, where the virus grows primarily in stromal cells but induces thymocyte apoptosis (P. G. Auwaerter et al., J. Virol. 70:3734- 3740, 1996). To begin to elucidate the roles of the C protein, V protein, and the 5' untranslated region of the F gene (F 5'UTR) in MV infection in vivo, the replication of strains bearing mutations of these genes was compared to that of the parent sequence-tagged Edmonston strain (EdTag). Growth curves show that mutants fall into two phenotypic classes. One class of mutants demonstrated kinetics of growth similar to that of EdTag, with decreased peak titers. The second class of mutants manifested peak titers similar to that of EdTag but had different replication kinetics. Abrogation of V expression led to delayed and markedly prolonged replication. Additionally, thymocyte survival was prolonged and implant architecture was preserved throughout the course of infection. In contrast, massive bystander thymocyte death occurred after infection with EdTag and all other mutants. A mutant which overexpressed V in Vero cells (V+) had the opposite phenotype of the A mutant not expressing V (V-). V+ grew more rapidly than EdTag with 100-fold-greater levels of virus production 3 days after infection. These results suggest that C, V, and the F 5'UTR are accessory factors required for efficient virus replication in vivo. In addition, thymocyte survival after V- infection suggests this protein may play multiple roles in pathogenesis of MV infection of thymus. Since these recombinant mutant viruses grew identically to the parent virus in Vero cells, the data show that thy/liv implants are an excellent model for investigating the determinants of MV virulence.

Original languageEnglish (US)
Pages (from-to)7754-7761
Number of pages8
JournalJournal of Virology
Volume72
Issue number10
StatePublished - Oct 1998

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Measles virus
Phenotype
mutation
phenotype
Mutation
Thymocytes
thymocytes
Growth
Infection
5' Untranslated Regions
mutants
infection
Genes
Thymus Gland
genes
Viruses
Virulence
5' untranslated regions
Vero Cells
Virus Diseases

ASJC Scopus subject areas

  • Immunology

Cite this

Recombinant measles viruses with mutations in the C, V, or F gene have altered growth phenotypes in vivo. / Valsamakis, Alexandra; Schneider, Henriette; Auwaerter, Paul G; Kaneshima, Hideto; Billeter, Martin A.; Griffin, Diane.

In: Journal of Virology, Vol. 72, No. 10, 10.1998, p. 7754-7761.

Research output: Contribution to journalArticle

Valsamakis, Alexandra ; Schneider, Henriette ; Auwaerter, Paul G ; Kaneshima, Hideto ; Billeter, Martin A. ; Griffin, Diane. / Recombinant measles viruses with mutations in the C, V, or F gene have altered growth phenotypes in vivo. In: Journal of Virology. 1998 ; Vol. 72, No. 10. pp. 7754-7761.
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abstract = "An understanding of the determinants of measles virus (MV) virulence has been hampered by the lack of an experimental model of infection. We have previously demonstrated that virulence phenotypes in human infections are faithfully reproduced by infection of human thymus/liver (thy/liv) implants engrafted into SCID mice, where the virus grows primarily in stromal cells but induces thymocyte apoptosis (P. G. Auwaerter et al., J. Virol. 70:3734- 3740, 1996). To begin to elucidate the roles of the C protein, V protein, and the 5' untranslated region of the F gene (F 5'UTR) in MV infection in vivo, the replication of strains bearing mutations of these genes was compared to that of the parent sequence-tagged Edmonston strain (EdTag). Growth curves show that mutants fall into two phenotypic classes. One class of mutants demonstrated kinetics of growth similar to that of EdTag, with decreased peak titers. The second class of mutants manifested peak titers similar to that of EdTag but had different replication kinetics. Abrogation of V expression led to delayed and markedly prolonged replication. Additionally, thymocyte survival was prolonged and implant architecture was preserved throughout the course of infection. In contrast, massive bystander thymocyte death occurred after infection with EdTag and all other mutants. A mutant which overexpressed V in Vero cells (V+) had the opposite phenotype of the A mutant not expressing V (V-). V+ grew more rapidly than EdTag with 100-fold-greater levels of virus production 3 days after infection. These results suggest that C, V, and the F 5'UTR are accessory factors required for efficient virus replication in vivo. In addition, thymocyte survival after V- infection suggests this protein may play multiple roles in pathogenesis of MV infection of thymus. Since these recombinant mutant viruses grew identically to the parent virus in Vero cells, the data show that thy/liv implants are an excellent model for investigating the determinants of MV virulence.",
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