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Evidence for both Lytic Replication and Tightly Regulated Human Herpesvirus 8 Latency in Circulating Mononuclear Cells, with Virus Loads Frequently below Common Thresholds of Detection

Elisa Martró,^1,2 Michael J. Cannon,¹ Sheila C. Dollard,¹ Thomas J. Spira,³ A. Scott Laney,^1, Chin-Yih Ou,³ and Philip E. Pellett^1,4*

Division of Viral and Rickettsial Diseases,¹ Division of AIDS, STD, and TB Laboratory Research, Centers for Disease ControlPrevention, Atlanta, Georgia,³ Microbiology Service, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain,² Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio⁴

Received 3 March 2004/ Accepted 15 June 2004

To address whether human herpesvirus 8 (HHV-8) DNA in peripheral blood mononuclear cells (PBMCs) might be the product of latent or lytic infection and to shed light on sporadic detection of HHV-8 DNA in individuals seropositive for the virus, we studied the frequency of infected cells, total virus load, and virus load per infected cell in PBMCs from men coinfected with HHV-8 and human immunodeficiency virus (HIV), some of whom had Kaposi's sarcoma. The low frequencies of infected cells detected (fewer than one per million cells in some individuals) suggest that the prevalence of the virus in circulating leukocytes was underestimated in previous studies that employed more conventional sampling methods (single, small-volume specimens). Mean virus loads ranged from 3 to 330 copies per infected PBMC; these numbers can represent much higher loads in individual lytically infected cells (>10³ genomes/cell) in mixtures that consist predominantly of latently (relatively few genomes) infected cells. The presence in some subjects of high HHV-8 mean genome copy numbers per infected cell, together with viral DNA being found in plasma only from subjects with positive PBMCs, supports earlier suggestions that the virus can actively replicate in PBMCs. In some individuals, mean virus loads were less than 10 genomes per infected cell, suggesting a tightly controlled purely latent state. HHV-8 genome copy numbers are substantially higher in latently infected cells derived from primary effusion lymphomas; thus, it appears that HHV-8 is able to adopt more than one latency program, perhaps analogous to the several types of Epstein-Barr virus latency.

Present address: Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213.

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