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Journal of Virology, January 2006, p. 710-722, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.710-722.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Entry into Epithelial and Endothelial Cells Depends on Genes UL128 to UL150 and Occurs by Endocytosis and Low-pH Fusion

Brent J. Ryckman,1 Michael A Jarvis,2 Derek D. Drummond,2 Jay A. Nelson,1,2 and David C. Johnson1*

Department of Molecular Microbiology and Immunology,1 Vaccine and Gene Therapy Institute, Oregon Health and Sciences University, Portland, Oregon 972392

Received 23 September 2005/ Accepted 24 October 2005

Human cytomegalovirus (HCMV) replication in epithelial and endothelial cells appears to be important in virus spread, disease, and persistence. It has been difficult to study infection of these cell types because HCMV laboratory strains (e.g., AD169 and Towne) have lost their ability to infect cultured epithelial and endothelial cells during extensive propagation in fibroblasts. Clinical strains of HCMV (e.g., TR and FIX) possess a cluster of genes (UL128 to UL150) that are largely mutated in laboratory strains, and recent studies have indicated that these genes facilitate replication in epithelial and endothelial cells. The mechanisms by which these genes promote infection of these two cell types are unclear. We derived an HCMV UL128-to-UL150 deletion mutant from strain TR, TR{Delta}4, and studied early events in HCMV infection of epithelial and endothelial cells, and the role of genes UL128 to UL150. Analysis of wild-type TR indicated that HCMV enters epithelial and endothelial cells by endocytosis followed by low-pH-dependent fusion, which is different from the pH-independent fusion with the plasma membrane observed with human fibroblasts. TR{Delta}4 displayed a number of defects in early infection processes. Adsorption and entry of TR{Delta}4 on epithelial cells were poor compared with those of TR, but these defects could be overcome with higher doses of virus and the use of polyethylene glycol (PEG) to promote fusion between virion and cellular membranes. High multiplicity and PEG treatment did not promote infection of endothelial cells by TR{Delta}4, yet virus particles were internalized. Together, these data indicate that genes UL128 to UL150 are required for HCMV adsorption and penetration of epithelial cells and to promote some early stage of virus replication, subsequent to virus entry, in endothelial cells.

* Corresponding author. Mailing address: 6366 Basic Sciences Building, Mail Code L-220, Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, 3181 Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-0834. Fax: (503) 494-6862. E-mail: johnsoda{at}ohsu.edu.

Journal of Virology, January 2006, p. 710-722, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.710-722.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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