HTLV-1 subverts the innate immune effector gene IRF7 by viral HBZ protein for oncogenesis
Interferon regulatory factors (IRFs) are innate immune transcription factors responsible for inducing the expression of type I interferons (IFN-I), which combat pathogen invasions via initiating the downstream Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. Among them, IRF7 plays a central role by forming heterodimers with IRF3 to initiate IFN-I production and is therefore frequently targeted by viruses to evade immune detection. Contrary to this common paradigm, we show that IRF7 is activated and upregulated by the retrovirus human T-cell leukemia virus type 1 (HTLV-1), via its oncoprotein HBZ. Moreover, IRF7 is highly expressed in HTLV-1 induced CD4 T-cell malignancy named adult T-cell leukemia/lymphoma (ATLL), and promotes the proliferation of infected cells both in vitro and in vivo. Intriguingly, HBZ is able to interfere with the interaction of IRF7 and IRF3, likely accounting for the inactive IFN-I pathway in ATLL cells. Unexpectedly, IRF7 was found to directly upregulate the transcription of STAT5B, a transcription factor of the JAK-STAT pathway frequently mutated in hematological malignancies. Together, these findings reveal a novel mechanism by which HTLV-1 hijacks a critical innate immune effector to sustain persistent infection and drive oncogenesis without activating antiviral IFN-I pathway.