Rhadinovirus Entry

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Kaposi’s sarcoma-associated herpesvirus (KSHV), the first human rhadinovirus, is etiologically linked to Kaposi’s sarcoma, primary effusion lymphoma and the multicentric Castleman’s disease. Its closest relative in old world monkeys is the rhesus rhadinovirus (RRV). Two strains of RRV, which differ considerably in their primary sequence of the glycoproteins H (gH) and L (gL) but are otherwise genetically almost identical, present a unique opportunity to shed light on the functions of the gH/gL complex during virus entry and replication. In this project, comparative analysis of these RRV variants and KSHV gH/gL will be conducted. Interaction of gH and gL with each other and with cellular receptors, which will be defined for RRV in the course of the funding period, will be analyzed. Interaction with and activation of the recently discovered KSHV gH/gL receptor EphA2 will be addressed. Functionally critical regions of gH/gL will be identified and the role of gH/gL for the tropism of RRV will be analyzed through the generation of recombinant mutant viruses both in cell culture and in a rhesus monkey infection model. Identification of conserved and non-conserved features of the gH/gL complex in these evolutionary closely related but divergent viruses will provide insights into the mechanisms of rhadinovirus entry. Moreover, elucidation of the functional domains of the rhadinovirus glycoproteins will point at potential target sites for intervention strategies and facilitate the development of rhadinoviral vectors for vaccines or gene therapy.