Chang, Henry and Ganem, Donald (2013) A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host & Microbe, 13 (4). pp. 429-440. ISSN 1931-3128

Abstract

Immunosuppression therapy following organ transplantation is a significant factor in the development and progression of Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced post-transplant Kaposi’s sarcoma (KS). Switching from cyclosporine to the mTOR inhibitor rapamycin is reported to promote KS regression without allograft rejection. Examining the underlying molecular basis for this clinical observation, we find that KSHV infection selectively upregulates mTOR signaling in primary human lymphatic endothelial cells (LEC) but not blood endothelial cells (BEC), and sensitizes LEC to rapamycin-induced apoptosis. Viral transcriptome analysis revealed that while infected BEC display conventional latency, KSHV-infected LEC support a radically different program involving widespread deregulation of both latent and lytic genes. ORF45, a lytic gene selectively expressed in infected LEC, is required for mTOR activation and critical for rapamycin sensitivity during KSHV infection. These studies reveal the existence of a unique herpesviral gene expression program corresponding to neither canonical latency nor lytic replication with important pathogenetic and therapeutic consequences.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/?term...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/?term...
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9985