Viral interferon regulatory factors inhibit the immune response following rhesus rhadinovirus infection

Kaposi’s sarcoma–associated herpesvirus (KSHV) and the related rhesus macaque rhadinovirus (RRV) encode a unique cluster of viral interferon regulatory factors (vIRFs). Using an RRV BAC clone, we generated a vIRF‑null virus to assess the role of these genes in infection and pathogenesis. Deletion of all eight vIRFs resulted in enhanced type I and II interferon responses, increased IRF‑3 nuclear accumulation, and profoundly reduced viral loads in rhesus macaques, along with stronger Th1 and T‑cell responses and diminished B‑cell hyperplasia. Individual vIRF analyses identified R6 as a key inhibitor of IRF‑3–mediated transcription. These findings underscore vIRFs’ central roles in immune evasion and suggest their potential as therapeutic targets.