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Journal of Virology, May 2008, p. 4793-4806, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01587-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Herpesvirus 8 Infects and Replicates in Primary Cultures of Activated B Lymphocytes through DC-SIGN{triangledown}

Giovanna Rappocciolo,1* Heather R. Hensler,1 Mariel Jais,1 Todd A. Reinhart,1 Amarendra Pegu,1 Frank J. Jenkins,1,2 and Charles R. Rinaldo1,2

Department of Infectious Diseases and Microbiology, Graduate School of Public Health,1 Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 152612

Received 20 July 2007/ Accepted 5 March 2008

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. Although latent HHV-8 DNA can be detected in B cells from persons with these cancers, there is little information on the replication of HHV-8 in B cells. Indeed, B cells are relatively resistant to HHV-8 infection in vitro. We have recently shown that DC-SIGN, a C-type lectin first identified on dendritic cells (DC), is an entry receptor for HHV-8 on DC and macrophages. We have also demonstrated previously that B lymphocytes from peripheral blood and tonsils express DC-SIGN and that this expression increases after B-cell activation. Here we show that activated blood and tonsillar B cells can be productively infected with HHV-8, as measured by an increase in viral DNA, the expression of viral lytic and latency proteins, and the production of infectious virus. The infection of B cells with HHV-8 was blocked by the pretreatment of the cells with antibody specific for DC-SIGN or with mannan but not antibody specific for xCT, a cystine/glutamate exchange transporter that has been implicated in HHV-8 fusion to cells. The infection of B cells with HHV-8 resulted in increased expression of DC-SIGN and a decrease in the expression of CD20 and major histocompatibility complex class I. HHV-8 could also infect and replicate in B-cell lines transduced to express full-length DC-SIGN but not in B-cell lines transduced to express DC-SIGN lacking the transmembrane domain, demonstrating that the entry of HHV-8 into B cells is related to DC-SIGN-mediated endocytosis. The role of endocytosis in viral entry into activated B cells was confirmed by blocking HHV-8 infection with endocytic pathway inhibitors. Thus, the expression of DC-SIGN is essential for productive HHV-8 infection of and replication in B cells.

* Corresponding author. Mailing address: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 604 Parran Hall, 130 De Soto St., Pittsburgh, PA 15261. Phone: (412) 383-9590. Fax: (412) 624-4953. E-mail: giovanna{at}pitt.edu

{triangledown} Published ahead of print on 12 March 2008.

Journal of Virology, May 2008, p. 4793-4806, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01587-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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