Kaposi’s sarcoma-associated herpesvirus reduces cellular myeloid differentiation primary response gene-88 (MyD88) expression via modulation of its RNA

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a human gamma herpesvirus associated with several human malignancies. The replication and transcription activator (RTA)is necessary and sufficient for the switch from KSHV latency to lytic replication. Interleukin 1(IL1) is a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Myeloid differentiation primary response gene 88 (MyD88) is an essential adaptor molecule for IL1 as well as most Toll-like receptors signaling. In this report, we identified a novel mechanism by which KSHV interferes with host inflammation and immunity. KSHV RTA specifically reduces the steady state protein levels of MyD88, and physiological levels of MyD88 are down regulated during KSHV lytic replication when RTA is expressed. The N-terminal region of RTA is required for the reduction of MyD88. Additional studies demonstrated that RTA targets MyD88 expression at the RNA level, inhibits RNA synthesis of MyD88, and may bind MyD88 RNA. Finally, RTA inhibits interleukin 1(IL1)-mediated activation of NF-kappaB (NF-κB). Because IL1 is abundant in KS microenvironment and inhibits KSHV replication, this work may expand our understanding on how KSHV evades host inflammation and immunity for its survival in vivo