The principal objective of the studies proposed here is to determine the role of the recently identified Kaposi's sarcoma-associated herpesvirus (KSHV) in the pathogenesis of AIDS-associated body cavity based lymphomas (AIDS-BCBLs). Since this virus is present in all AIDS-BCBLs examined thus far, and no other type of lymphoma, we will specifically study the elements of KSHV which might be responsible for transformation as well as for the unusual phenotype of these lymphoid neoplasms. Because the portions of KSHV which have been cloned and sequenced thus far have shown homology and collinearity with Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), we will take advantage of methodologies previously established for the study of the role of these viruses in the development of malignant lymphomas. Specifically, we will 1) determine the presence and type of transforming genes in KSHV. This will be achieved by cloning and sequencing larger portions of the KSHV genome in order to obtain genes homologous to those in EBV and HVS which are relevant in lymphoid transformation. We will 2) determine the ability of KSHV to infect lymphoid cells in vitro. In order to do this, we will use methods previously established for other herpesviruses, i.e. EBV, such as co- cultivation of lethally irradiated infected cells with the target cells. After transmission is achieved we will 3) determine the oncogenic effect of KSHV in lymphoid cells. For this purpose we will assess the phenotypic and biologic differences, including growth rate, serum requirements, growth in soft agar and tumorigenesis in nude mice, between the infected and uninfected cells. We will attempt to identify the phenotypic and biologic features of infected cells which may be related to the growth pattern of AIDS-BCBL, that is, as malignant effusions. Subsequently, we will 4) investigate the genes responsible for the effect(s) KSHV might have in lymphoid transformation. In order to do this, gene transfer experiments will be performed using genes homologous to those in EBV and KSHV which are already known to be relevant for lymphoid transformation. In the event that genes without homologies to EBV or HVS are identified, they will also be tested for possible effects in lymphoid transformation. Thus, we will take advantage of mostly """"""""classic"""""""" methods as well as the understanding of similar viruses, to assess the role of KSHV in the pathogenesis of AIDS-BCBLs. This will lead to a better understanding of a novel human herpesvirus which appears to be playing a relevant role in the malignant transformation of a subset of AIDS-associated lymphomas.
| Sun, Shao-Cong; Cesarman, Ethel (2011) NF-?B as a target for oncogenic viruses. Curr Top Microbiol Immunol 349:197-244 |
| Di Bartolo, Daniel L; Hyjek, Elizabeth; Keller, Shannon et al. (2009) Role of defective Oct-2 and OCA-B expression in immunoglobulin production and Kaposi's sarcoma-associated herpesvirus lytic reactivation in primary effusion lymphoma. J Virol 83:4308-15 |
