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

被引:93
作者
Valsamakis, A
Schneider, H
Auwaerter, PG
Kaneshima, H
Billeter, MA
Griffin, DE
机构
[1] Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA
[2] Univ Zurich, Zurich, Switzerland
[3] SyStemix, Palo Alto, CA USA
关键词
D O I
10.1128/JVI.72.10.7754-7761.1998
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:7754 / 7761
页数:8
相关论文
共 52 条
  • [1] Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice
    Aldrovandi, GM
    Zack, JA
    [J]. JOURNAL OF VIROLOGY, 1996, 70 (03) : 1505 - 1511
  • [2] Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis
    Auwaerter, PG
    Kaneshima, H
    McCune, JM
    Wiegand, G
    Griffin, DE
    [J]. JOURNAL OF VIROLOGY, 1996, 70 (06) : 3734 - 3740
  • [3] MEASLES VIRUS-P GENE CODES FOR 2 PROTEINS
    BELLINI, WJ
    ENGLUND, G
    ROZENBLATT, S
    ARNHEITER, H
    RICHARDSON, CD
    [J]. JOURNAL OF VIROLOGY, 1985, 53 (03) : 908 - 919
  • [4] HIV INDUCES THYMUS DEPLETION INVIVO
    BONYHADI, ML
    RABIN, L
    SALIMI, S
    BROWN, DA
    KOSEK, J
    MCCUNE, JM
    KANESHIMA, H
    [J]. NATURE, 1993, 363 (6431) : 728 - 732
  • [5] DRAMATIC INTERSTRAIN DIFFERENCES IN THE REPLICATION OF HUMAN CYTOMEGALOVIRUS IN SCID-HU MICE
    BROWN, JM
    KANESHIMA, H
    MOCARSKI, ES
    [J]. JOURNAL OF INFECTIOUS DISEASES, 1995, 171 (06) : 1599 - 1603
  • [6] The sendai paramyxovirus accessory C proteins inhibit viral genome amplification in a promoter-specific fashion
    Cadd, T
    Garcin, D
    Tapparel, C
    Itoh, M
    Homma, M
    Roux, L
    Curran, J
    Kolakofsky, D
    [J]. JOURNAL OF VIROLOGY, 1996, 70 (08) : 5067 - 5074
  • [7] THE RULE OF 6, A BASIC FEATURE FOR EFFICIENT REPLICATION OF SENDAI VIRUS DEFECTIVE INTERFERING RNA
    CALAIN, P
    ROUX, L
    [J]. JOURNAL OF VIROLOGY, 1993, 67 (08) : 4822 - 4830
  • [8] Preferential initiation at the second AUG of the measles virus F mRNA: A role for the long untranslated region
    Cathomen, T
    Buchholz, CJ
    Spielhofer, P
    Cattaneo, R
    [J]. VIROLOGY, 1995, 214 (02) : 628 - 632
  • [9] CELL-FUSION BY THE ENVELOPE GLYCOPROTEINS OF PERSISTENT MEASLES VIRUSES WHICH CAUSED LETHAL HUMAN BRAIN DISEASE
    CATTANEO, R
    ROSE, JK
    [J]. JOURNAL OF VIROLOGY, 1993, 67 (03) : 1493 - 1502
  • [10] MEASLES-VIRUS EDITING PROVIDES AN ADDITIONAL CYSTEINE-RICH PROTEIN
    CATTANEO, R
    KAELIN, K
    BACZKO, K
    BILLETER, MA
    [J]. CELL, 1989, 56 (05) : 759 - 764