ORF48 is required for optimal lytic replication of Kaposi's Sarcoma-Associated Herpesvirus.

Kaposi sarcoma-associated herpesvirus (KSHV) causes persistent infection in a host that leads to two deadly cancers, Kaposi Sarcoma and Primary Effusion Lymphoma, especially in immunocompromised people. Unfortunately, there is no vaccine or viral-specific treatment for KSHV-related diseases, due to our limited knowledge of detailed immune evasion strategies by KSHV. KSHV blocks multiple immune pathways to maintain its lifelong infection, one of which is the DNA-sensing cGAS-STING pathway. Here, we reported that ORF48, a KSHV-encoded STING inhibitor is required for optimal KSHV lytic reactivation and viral production. A successful KSHV infection requires both intact ORF48 DNA and mRNA at different stages of its lytic life cycle. Further study reveals that ORF48 binds to STING and blocks STING-dependent innate immunity, and additional mechanisms may contribute to its role in lytic replication. Our findings provide insight into viral immune evasion strategies, which would contribute to a better understanding of all viral diseases.