ORF74 is a constitutively active chemokine receptor encoded by the Kaposi's Sarcoma-associated Herpes Virus (KSHV), or Human Herpes Virus 8 (HHV8). Our group has shown that expression of ORF74 in hematopoietic cells of transgenic mice leads to the development of angioproliferative lesions that resemble those seen in Kaposi's sarcoma (KS). The lesions are characterized by large numbers of CD34+ endothelial cells, vascular channels filled with red cells, and inflammatory cells, are observed in ears, limbs and tail, and progress from erythematous lesions to nodules and tumors within 6 months. We hypothesize that ORF74 induces angioproliferation indirectly by activating expression of angiogenic factors within the lesions. We base our hypothesis on two sets of findings: 1) ORF74 can trigger expression of angiogenic molecules in vitro, and 2) ORF74 - expressing cells, similar to what is observed in KS, represent a small number of the total cells in the transgenic lesions. However, the nature and timing of the expression of these factors in vivo, the phenotype of the cell driving the disease, and the overall relevance of ORF74 to disease development in mice and humans are currently unknown. To understand how ORF74 induces angioproliferation, our laboratory has now developed a conditional transgenic system, in which expression of ORF74 is positively controlled by the administration of doxycycline (DOX). Upon treatment with DOX, the transgenic animals develop angiogenic lesions in the ears that progress to nodules and tumors. The physical distribution and histological characteristics of the lesions are similar to those presented in the model previously described by our group. This conditional transgenic system will allow the characterization of the cellular and molecular events associated with the expression of ORF74, and will enable us to understand more fundamentally the role played by ORF74 in the angioproliferation. Specifically, we propose:
AIM 1. To define the cellular and molecular events triggered by the expression of ORF74.
AIM 2. To define the cell type responsible for the development of the angioproliferative disease.
AIM 3. To determine whether ORF74 expression is required for maintenance and progression of the angioproliferative disease.
| Grisotto, Marcos G; Garin, Alexandre; Martin, Andrea P et al. (2006) The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells. J Clin Invest 116:1264-73 |
| Jensen, Kristian K; Manfra, Denise J; Grisotto, Marcos G et al. (2005) The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma. J Immunol 174:3686-94 |
