Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is associated,vith three proliferative diseases ranging from viral cytokine-in duced hyperplasia to monoclonal neoplasia: multicentric Castleman's disease (CD), Kaposi's sarcoma (KS), and primary effusion lymphoma (PEL). Here we report a new latency-associated 1,704-bp KSHV spliced gene belonging to a c luster of KSHV sequences having homology to the interferon regulatory facto r (IRF) family of transcription factors. ORFK10.5 encodes a protein, latenc y-associated nuclear antigen 2 (LANA2), which is expressed in KSHV-infected hematopoietic tissues, including PEL and CD but not KS lesions. LANA2 is a bundantly expressed in the nuclei of cultured KSHV-infected B cells. Transc ription of K10.5 in PEL cell cultures is not inhibited by DNA polymerase in hibitors nor significantly induced by phorbol ester treatment. Unlike LANA1 , LANA2 does not elicit a serologic response from patients with KS, PEL, or CD as measured by Western blot hybridization. Both KSHV vIRF1 (ORFK9) and LANA2 (ORFK10,5) appear to have arisen through gene duplication of a captur ed cellular IRF gene. LANA2 is a potent inhibitor of p53-induced transcript ion in reporter assays. LANA2 antagonizes apoptosis due to p53 overexpressi on in p53-null SAOS-2 cells and apoptosis due to doxorubicin treatment of w ild-type p53 U2OS cells, While LANA2 specifically interacts with amino acid s 290 to 393 of p53 in glutathione S-transferase pull-down assays, we were unable to demonstrate LANA2-p53 interaction in vivo by immunoprecipitation. These findings show that KSHV has tissue-specific latent gene expression p rograms and identify a new latent protein which may contribute to KSHV tumo rigenesis in hematopoietic tissues via p53 inhibition.