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Human Herpesvirus-8 Infection of Primary Pulmonary Microvascular Endothelial Cells

¹ Division of Pulmonary Sciences and Critical Care Medicine, and ³ Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado; and ² Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Todd M. Bull, M.D., University of Colorado, Denver Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine C-272, 4200 E. 9th Avenue, Denver, CO 80207. E-mail: Todd.Bull{at}uchsc.edu

Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) has been described. We hypothesize that HHV-8 infection of pulmonary microvascular endothelial cells results in an apoptotic-resistant phenotype characteristic of severe pulmonary arterial hypertension. Our objective was to investigate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells in vitro and characterize the phenotypic effect of this infection. Human pulmonary microvascular endothelial cells were exposed to HHV-8 using two methods (direct virus and co-culture technique). The presence of lytic and latent infection was confirmed. Changes in endothelial cell gene and protein expression and effects on cellular apoptosis were measured. HHV-8 can both lytically and latently infect primary human pulmonary microvascular endothelial cells in vitro. HHV-8 infection results in significant changes in gene expression, including alterations of pathways important to cellular apoptosis. HHV-8 infection also alters expression of genes integral to the bone morphogenic protein pathway, including down-regulation of bone morphogenic protein-4. Other genes previously implicated in the development of PAH are affected by HHV-8 infection, and cells infected with HHV-8 are resistant to apoptosis.

Key Words: HHV-8 • endothelial cells • pulmonary hypertension

CLINICAL RELEVANCE This article suggests mechanisms by which human herpesvirus (HHV)-8 may result in pathology in the pulmonary vasculature. It provides insight into the means by which HHV-8 could play a role in the development of some forms of pulmonary hypertension.