A Unique Herpesviral Transcriptional Program in KSHV-Infected Lymphatic Endothelial Cells Leads to mTORC1 Activation and Rapamycin Sensitivity

Henry H Chang and Don Ganem. Cell Host Microbe (2013) 4, 429-440

Speaker: Chieh-Yu Lin (林倢妤)                          Time: 15:00~16:00, Dec. 11, 2013

Commentator: Dr. Yao Chang (張堯老師)           Place: Room 601

Abstract:

Kaposi’s sarcoma arising from endothelial cells infected with Kaposi’s sarcoma-associated herpesvirus (KSHV) are commonly observed in patients with immunodeficiency [1]. In patients who have received organ transplantation, immunosuppressive drugs are used to prevent allograft rejection, but they also increase the risk of KS lesion formation. A clinical study found that replacement of an immunosuppressive drug with rapamycin, an mTOR inhibitor, promotes KS lesion regression without allograft rejection [2]. However, the mechanism underlying this phenomenon is unclear. To study this issue, lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) were latently infected with KSHV and treated with rapamycin. The authors found that rapamycin selectively induced apoptosis in KSHV-infected LECs, but not BECs. Consistent with this result, mTOR was selectively activated in LECs, and the activation of mTOR was mediated by ERK2/RSK1 activation. They further found that latently infected LECs abnormally expressed several lytic genes of KSHV, including ORF45, which is responsible for the activation of ERK2/RSK1. However, rapamycin treatment failed to induce apoptosis of uninfected LECs ectopically expressing ORF45, indicating that ORF45 alone is not sufficient to increase rapamycinsensitivity in infected LECs. Collectively, the authors found that LECs latently infected with KSHV exhibited dysregulated expression of lytic genes, while infected BECs did not. In addition, ORF45 is necessary to sensitize the infected LECs to rapamycin-mediated apoptosis. This finding provides another therapeutic strategy to KS.

References:

1.     Dezube BJ. Clinical presentation and natural history of AIDS-related Kaposi’s sarcoma. Hematol Oncol Clin North Am (1996) 10, 1023-1029.

2.    Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, and Grandaliano G. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N EnglJ Med (2005) 352, 1317-1323.