Abstract
Human herpesvirus 8 (HHV-8) is associated with Kaposi’s sarcoma, body cavity-based lymphoma, and Castleman’s disease. Adenoviral (Ad) E1A proteins regulate the activity of cellular and viral promoters/enhancers and transcription factors and can suppress tumorigenicity of human cancers. As (i) HHV-8 and Ad may co-exist in immunocompromised patients and (ii) E1A might be considered as therapeutic transgene for HHV-8-associated neoplasms we investigated whether the promoter of the latency-associated nuclear antigen (LANAp) controlling expression of vCyclin, vFLIP, and LANA proteins required for latent type infection is regulated by E1A. Transfection experiments in MV3 melanoma cells revealed activation of the LANAp by Ad5 E1A constructs containing an intact N terminus (aa 1-119). In particular, an Ad12 E1A mutant, Spm2, lacking six consecutive alanine residues in the “spacer” region activated the HHV-8 promoter about 15-fold compared to vector controls. In summary, we report the activation of the LANAp by E1A as a novel interaction of E1A with a viral promoter. These data may have relevance for the management of viral infections in immunocompromised patients. A role for E1A as a therapeutic in this context remains to be defined.
Highlights
Human herpesvirus 8 (HHV-8) was discovered in Kaposi’s sarcoma (KS) biopsy samples [1,2,3], primary effusion lymphomas (PEL) [4], multicentric Castleman’s disease [5], and plasmablastic lymphomas [6] and has been linked to pathogenesis of these disorders
To confirm that the LANAp operates in MV3 melanoma cells, we assessed its ability to drive expression of a reporter gene in transiently transfected MV3 cells
Studies to define regulatory elements of the LANAp and other latency-associated HHV-8 genes have been previously performed by others in a variety of adherent, non Blymphoid cell types, including HeLa, HEK293, and SLK cells demonstrating the general usability of these systems [52, 54, 55]
Summary
Human herpesvirus 8 (HHV-8) was discovered in Kaposi’s sarcoma (KS) biopsy samples [1,2,3], primary effusion lymphomas (PEL) [4], multicentric Castleman’s disease [5], and plasmablastic lymphomas [6] and has been linked to pathogenesis of these disorders. Divergent regions contain unique viral proteins, some of which mimic cell cycle regulation and signal transduction proteins required for lytic replication and latency [7]. In KS, HHV8 persists latently in the majority of tumor cells with fewer than 5% of cells undergoing spontaneous lytic replication [9, 10]. Mapping of transcripts involved in latency pointed to responsible genes such as ORF73, ORF72 encoding vCyc, a functional viral cyclin, and ORFK13 encoding vFLIP, a protein [11, 12] likely to have anti-apoptotic activity and contribute to the tumor phenotype [13]
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