RHESUS HHV8 HOMOLOGUE IN AIDS-RELATED MALIGNANCIES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. My laboratory is utilizing the simian immunodeficiency virus (SIV)/rhesus rhadinovirus (RRV)/rhesus macaque (RM) animal model to elucidate how RRV is able to recapitulate many of the lymphoproliferative disorders (LPD) that human herpesvirus 8 (HHV8) is capable of inducing in AIDS patients. These include multicentric Castleman's disease (MCD) and non-Hodgkin's lymphoma (NHL). During the past year we have made significant progress, building upon our success with the infectious and pathogenic rhesus rhadinovirus bacterial artificial chromosome (BAC). This RRV-BAC produces infectious virus (BAC-derived virus) in transfected rhesus fibroblasts that is capable of inducing B cell hyperplasia in SIV-infected RM. More importantly, SIV-infected RM experimentally infected with the BAC-derived virus develops persistent lymphadenopathy, much like wild-type RRV infection. These are important and essential studies which will lead to the identification of viral determinants of pathogenesis. Our initial focus has been on those viral ORFs and macromolecules that are conserved between HHV8 and RRV. These include the viral interferon regulatory factors (vIRFs), viral CD200 (vCD200) homologue and the viral encoded miRNAs. To this end, we have created three recombinants that lack the ability to express these specific viral ORFs. The recombinant lacking the eight vIRFs is capable of growth in cell culture, but is unable to replicate in experimentally infected animals. The second recombinant contains a nonsense mutation in the vCD200. This recombinant grows well in cell culture and is capable of establishing a persistent infection in animals. Interestingly, these animals have higher viral loads than animals infected with wild-type virus and present with RRV-associated disease.