Human Herpesvirus-8 Infection of Primary Pulmonary Microvascular Endothelial Cells

Abstract

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.

Viral infection and pulmonary hypertension: is there an association?

“…Although we found the LANA-1 protein in the lungs of patients with IPAH [82], the work is controversial and has not been supported by serologic studies, although one other group found similar LANA staining in a similar percentage of lungs from patients with IPAH [83]. The work by Bull et al [90] and Durrington et al [93] regarding the consequences of HHV-8 infection of endothelial cells suggests that HHV-8 is a potential viral cause of PAH [90,93]. That HHV-8 is not found in PAH in other regions does not negate its possible role in the development of PAH.…”

“…Bull et al recently used an in vitro model of HHV-8 infection of pulmonary endothelial cells and found that not only can HHV-8 infect primary human pulmonary microvascular endothelial cells, but that infection leads to alterations of gene and protein expression [90]. BMPR1a and BMP4 -both part of the TGF-b signaling pathway -are decreased following HHV-8 infection.…”

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

“…Recently, conclusive evidence that idiopathic PAH pulmonary artery EC have a hyperproliferative apoptosisresistant phenotype compared with cells from control lungs has been shown using cell proliferation, DNA synthesis, and the evaluation of cell death pathways (42). Likewise, human herpes virus 8 (HHV-8) infection of pulmonary microvascular EC results in an apoptotic-resistant phenotype characteristic of severe PAH (43), although it is unclear whether HHV-8 has a pathogenetic role in idiopathic PAH (44)(45)(46). Moreover, dysfunctional endothelial progenitor cells, which are hyperproliferative with impaired ability to form vascular networks, are involved in the vascular remodeling associated with PAH (47).…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…Several viral infections, including HIV, HHV-8, and hepatitis B and C, are implicated in producing increased PAH incidence and prevalence [109][110][111][112][113][114]. It is estimated that HIV infection increases the prevalence of PAH approximately 2500-fold [110].…”