An Endothelial Cell-Specific Requirement for the UL133-UL138 Locus of Human Cytomegalovirus for Efficient Virus Maturation

被引:38
作者
Bughio, Farah [1 ]
Elliott, David A. [2 ]
Goodrum, Felicia [1 ,3 ]
机构
[1] Univ Arizona, Inst BIO5, Tucson, AZ 85721 USA
[2] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA
[3] Univ Arizona, Dept Immunobiol, Tucson, AZ USA
关键词
CYTOPLASMIC COMPARTMENT; EPITHELIAL-CELLS; IN-VITRO; INFECTION; TROPISM; ENTRY; PROTEIN; HCMV; REPLICATION; ENVELOPMENT;
D O I
10.1128/JVI.02510-12
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human cytomegalovirus (HCMV) infects a variety of cell types in humans, resulting in a varied pathogenesis in the immuno-compromised host. Endothelial cells (ECs) are considered an important target of HCMV infection that may contribute to viral pathogenesis. Although the viral determinants important for entry into ECs are well defined, the molecular determinants regulating postentry tropism in ECs are not known. We previously identified the UL133-UL138 locus encoded within the clinical strain-specific ULb' region of the HCMV genome as important for the latent infection in CD34(+) hematopoietic progenitor cells (HPCs). Interestingly, this locus, while dispensable for replication in fibroblasts, was required for efficient replication in ECs infected with the TB40E or fusion-inducing factor X (FIX) HCMV strains. ECs infected with a virus lacking the entire locus (UL133-UL138(NULL) virus) complete the immediate-early and early phases of infection but are defective for infectious progeny virus production. ECs infected with UL133-UL138(NULL) virus exhibited striking differences in the organization of intracellular membranes and in the assembly of mature virions relative to ECs infected with wild-type (WT) virus. In UL133-UL138(NULL) virus- infected ECs, Golgi stacks were disrupted, and the viral assembly compartment characteristic of HCMV infection failed to form. Further, progeny virions in UL133-UL138(NULL) virus-infected ECs inefficiently acquired the virion tegument and secondary envelope. These defects were specific to infection in ECs and not observed in fibroblasts infected with UL133-UL138(NULL) virus, suggesting an EC-specific requirement for the UL133-UL138 locus for late stages of replication. To our knowledge, the UL133-UL138 locus represents the first cell-type-dependent, postentry tropism determinant required for viral maturation.
引用
收藏
页码:3062 / 3075
页数:14
相关论文
共 89 条
[1]   Role of human cytomegalovirus UL131 A in cell type-specific virus entry and release [J].
Adler, Barbara ;
Scrivano, Laura ;
Ruzcics, Zsolt ;
Rupp, Brigitte ;
Sinzger, Christian ;
Koszinowski, Ulrich .
JOURNAL OF GENERAL VIROLOGY, 2006, 87 :2451-2460
[2]   Endothelial cells in human cytomegalovirus infection: One host cell out of many or a crucial target for virus spread? [J].
Adler, Barbara ;
Sinzger, Christian .
THROMBOSIS AND HAEMOSTASIS, 2009, 102 (06) :1057-1063
[3]   RISK-FACTORS FOR CHRONIC REJECTION IN RENAL-ALLOGRAFT RECIPIENTS [J].
ALMOND, PS ;
MATAS, A ;
GILLINGHAM, K ;
DUNN, DL ;
PAYNE, WD ;
GORES, P ;
GRUESSNER, R ;
NAJARIAN, JS ;
FERGUSON ;
PAUL ;
SCHAFFER .
TRANSPLANTATION, 1993, 55 (04) :752-757
[4]   Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and β1 and β3 integrins [J].
Bentz, Gretchen L. ;
Yurochko, Andrew D. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (14) :5531-5536
[5]   Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV [J].
Bentz, Gretchen L. ;
Jarquin-Pardo, Marta ;
Chan, Gary ;
Smith, M. Shane ;
Sinzger, Christian ;
Yurochko, Andrew D. .
JOURNAL OF VIROLOGY, 2006, 80 (23) :11539-11555
[6]   Cytomegalovirus: pathogen, paradigm, and puzzle [J].
Boeckh, Michael ;
Geballe, Adam P. .
JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (05) :1673-1680
[7]   Human cytomegalovirus strain toledo lacks a virus-encoded tropism factor required for infection of aortic endothelial cells [J].
Bolovan-Fritts, C ;
Wiedeman, JA .
JOURNAL OF INFECTIOUS DISEASES, 2001, 184 (10) :1252-1261
[8]  
Bolovan-Fritts CA, 2002, J CLIN VIROL, V25, pS97
[9]   IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin [J].
Botto, Sara ;
Streblow, Daniel N. ;
DeFilippis, Victor ;
White, Laura ;
Kreklywich, Craig N. ;
Smith, Patricia P. ;
Caposio, Patrizia .
BLOOD, 2011, 117 (01) :352-361
[10]  
Britt W, 2008, CURR TOP MICROBIOL, V325, P417