: Kaposi's sarcoma (KS) is a common malignancy associated with AIDS and is characterized by the presence of spindle-shaped cells, inflammatory cells, and a high degree of vascularization. A new oncogenic herpesvirus was discovered in KS tumors, named KS herpesvirus (KSHV). We have identified two homologs of KSHV in retroperitoneal fibromatosis (RF), a malignancy of macaques with similarities to KS. We are currently characterizing the RF herpesviruses (RFHV) with the goal of developing an animal model of KS. KSHV has been shown to infect B cells, endothelial cells and KS spindle-shaped cells. Although much research has been done to characterize KSHV genes involved in cell growth and transformation, little has been done to study the mode of infection of KSHV including the characterization of viral and cellular receptors. We have cloned and sequenced the glycoprotein B (gB) genes for KSHV and RFHV and have initiated functional characterization. KSHV gB is present in the virion suggesting that it could be involved with virus-cell interactions including binding and penetration, as has been shown for the gBs of other herpesviruses. In this application, we propose to study the role of gB from KSHV and the macaque homolog RFHV in binding and infection of host target cells. We have identified conserved integrin binding RGD motifs in both viral gBs that have allowed us to make predictions regarding viral-cell interactions, putative viral receptors and potential signaling pathways which might play roles in KSHV infection, cell tropism and KS pathogenesis. The identification of viral and cellular receptors for KSHV could have important implications in developing analytical and therapeutical modalities for the treatment KS, a malignancy of increasingly world-wide importance. Our goals are to develop an in vitro model system to determine whether gB functions in this or other pathways in KSHV infection and develop an animal model for further study of KS-like malignancies in vive. Specifically, we will determine 1) whether the RGD motifs in KSHV and RFHV gBs mediate binding to cellular integrin receptors, 2) Determine whether KSHV attachment/entry is mediated by RGD-gB interactions with cell surface integrins and 3) Determine whether binding of viral gB to host cells can affect cellular processes and intracellular signaling.
| Garrigues, H Jacques; Rubinchikova, Yelena E; Dipersio, C Michael et al. (2008) Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi's sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor. J Virol 82:1570-80 |
