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Journal of Virology, March 2002, p. 2440-2448, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2440-2448.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

De Novo Infection and Serial Transmission of Kaposi's Sarcoma-Associated Herpesvirus in Cultured Endothelial Cells

*** Michael Lagunoff,1,{dagger} Jill Bechtel,1 Eleni Venetsanakos,2 Anne-Marie Roy,1 Nancy Abbey,3 Brian Herndier,3 Martin McMahon,2 and Don Ganem1*

Departments of Microbiology and Medicine,1 Pathology, Howard Hughes Medical Institute,3 UCSF Comprehensive Cancer Center, University of California, San Francisco, California 94143-04142

Received 8 October 2001/ Accepted 28 November 2001

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is central to the pathogenesis of the endothelial neoplasm Kaposi's sarcoma (KS) and is also linked to the rare B-cell tumor known as primary effusion lymphoma (PEL). Latently infected PEL cell lines can be induced to enter the lytic cycle and produce KSHV virions. However, such cells do not support de novo infection or serial propagation of KSHV. These limitations have prevented the development of systems for the genetic analysis of KSHV and have impeded a deeper understanding of KS pathogenesis. Here we show that human dermal microvascular endothelial cells immortalized by expression of telomerase can be readily infected by KSHV virions produced by PEL cells. Infection is predominantly latent, but a small subpopulation enters the lytic cycle spontaneously. Phorbol ester (tetradecanoyl phorbol acetate [TPA]) treatment of latently infected cells leads to enhanced induction of lytic KSHV replication, resulting in foci of cytopathic effect. There is no cytopathic effect or viral DNA expansion when infected TIME cells (telomerase-immortalized microvascular endothelial cells) are TPA induced in the presence of phosphonoacetic acid (PAA), an inhibitor of herpesvirus replication. Supernatants from phorbol-induced cultures transfer latent KSHV infection to uninfected cells, which can likewise be induced to undergo lytic replication by TPA treatment, and the virus can be further serially transmitted. Serial passage of the virus in TIME cells is completely inhibited when TPA treatment is done in the presence of PAA. Latently infected endothelial cells do not undergo major morphological changes or growth transformation, and infection is lost from the culture upon serial passage. This behavior faithfully recapitulates the behavior of spindle cells explanted from primary KS biopsies, strongly supporting the biological relevance of this culture system. These findings suggest that either the stability or the growth-deregulatory potential of the KSHV latency program in endothelial cells is more limited than might be predicted by analogy with other oncogenic viruses.

* Corresponding author. Mailing address: Department of Microbiology, Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Ave., HSE 405, Box 0414, San Francisco, CA 94143-0414. Phone: (415) 476-2826. Fax: (415) 476-0939. E-mail: ganem{at}cgl.ucsf.edu.

{dagger} Present address: Department of Microbiology, University of Washington, Seattle, WA 98195.

Journal of Virology, March 2002, p. 2440-2448, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2440-2448.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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