Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Abstract

IntroductionKaposi sarcoma-associated herpesvirus (KSHV; also human herpesvirus-8) is implicated in all clinical forms of KS 1,2 as well as the lymphoproliferative disorders primary effusion lymphoma (PEL) 3,4 and multicentric Castleman disease (MCD). 5 Endothelial cells harbor the KSHV genome in vivo, 1,6,7 are permissive for virus infection in vitro, [8][9][10][11] and are thought to be the precursors of spindle cells. [12][13][14][15] We and others have shown that in vitro infection of human dermal microvascular endothelial cells (DMVECs) with KSHV induces a spindle cell morphology and characteristics of a transformed phenotype, including loss of contact inhibition and growth in soft agar. [8][9][10][11] Because explanted KS cells fail to maintain the KSHV genome following serial passage, 16,17 in vitro infection of DMVECs has proved to be an invaluable tool for the study of KSHV pathogenic mechanisms. 18,19 KSHV, like other herpesviruses, has a substantial coding capacity that includes viral genes unique to this human pathogen, genes that share homology with other members of the herpesviridae, as well as genes that appear to have originated in the host genome. 20,21 Of note, at least 3 of these gene products, vFLIP (viral Fas-associating protein with death domain-like interleukin-1␤ [IL-1␤]-converting enzyme [FLICE]-inhibitory protein), viral cyclin (vCYC), and latency-associated nuclear antigen (LANA), are believed to comprise the viral latency expression program and are consistently expressed in all virally infected cells in KS, PEL, and MCD. [22][23][24] The gene product of open reading frame 71 (ORF 71), vFLIP, is thought to play an important role in prevention of apoptotic cell death. 25 The activity of a homolog of cellular cyclin D, vCYC (ORF 72), 26 together with the modulation of cellular transcription wrought by LANA (ORF 73) 27 is thought to be involved in KSHV-induced host cell transformation. Additionally, LANA is indispensable for maintenance of the viral genome. 28 Other gene products, such as viral G-protein-coupled receptor (vGCR) 29,31 are classified as lytic gene products and are expressed in only a minority of cells in vivo. [32][33][34] Although reactivation of KSHV from the latent state and subsequent completion of the viral lytic expression cascade is incompatible with survival of a host cell, lytic gene products are thought to have paracrine influences on both latently infected and uninfected cells and are thus considered vital for lesion development. 35 We have used our previously described in vitro KS model to dissect viral mechanisms of pathogenesis. 18,19 The salient features of our model include recapitulation of KS cell physiology, including spindle cell formation, loss of contact inhibition, and anchoragedependent growth restriction; long-term propagation of predominantly latently infected cells; and the ability to generate ageand passage-matched KSHV-infected and uninfected cultures. 11 This system has been amenable to gene expression profiling by cDNA microarrays and has ...

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

“…The IR joins a growing list of host cell proteins essential for the transformed phenotype in ECs infected by KSHV in vitro (Moses et al, 2002;McAllister et al, 2004;Raggo et al, 2005). It seems that multiple mechanisms are required to support the postconfluent growth of DMVEC.…”

“…Upon infection with KSHV, E-DMVECs develop a spindle cell phenotype, lose contact inhibition, form foci when cultured postconfluence and acquire the ability to form colonies in soft agar. The E-DMVEC system has thus been extremely useful for evaluating changes in the cellular transcriptome and proteome, ultimately leading to the identification of both known as well as novel oncogenes that are likely to be involved in KS tumorigenesis (Moses et al, 2002;McAllister et al, 2004;Raggo et al, 2005).…”

Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

“…Interestingly, a recent study has shown that HO-1 expression and activity are induced by an angiogenic oncovirus, the Kaposi sarcoma-associated herpesvirus (KSHV), in endothelial cells. Besides, elevated levels of the enzyme are detectable in biopsy tissue from oral AIDS-Kaposi sarcoma lesions (12).…”

The pleiotropic effects of Kaposi's sarcoma herpesvirus

“…Suppression of RDC1 and neuritin gene expression by antisense oligonucleotides or siRNA reversed the morphological changes and increased proliferation induced by KSHV in DMVECs and also the growth in soft agar and tumourigenicity in the nude mouse model of 3T3 mouse fibroblasts stably transfected with either RDC1 or neuritin [80]. Haem oxygenase 1 (HO-1) is among several other cellular genes induced in cultured endothelial cells by latent KSHV infection [78][79][80][81][82][83] and is also expressed in KSHV-infected spindle cells in KS lesions [83]. The HO-1 inhibitor chromium mesoporphyrin IX inhibits haem-induced proliferation of KSHV-infected, but not uninfected, DMVECs, suggesting a role for HO-1 in the proliferation of KSHV-infected spindle cells [83].…”

“…Haem oxygenase 1 (HO-1) is among several other cellular genes induced in cultured endothelial cells by latent KSHV infection [78][79][80][81][82][83] and is also expressed in KSHV-infected spindle cells in KS lesions [83]. The HO-1 inhibitor chromium mesoporphyrin IX inhibits haem-induced proliferation of KSHV-infected, but not uninfected, DMVECs, suggesting a role for HO-1 in the proliferation of KSHV-infected spindle cells [83]. It is likely that other KSHV-induced cellular genes also contribute to the development of KS spindle cells.…”