HTLV-1 subverts the innate immune effector gene IRF7 by viral HBZ protein for oncogenesis.

Abstract

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, suppressing IFN-I pathway activation. On the other hand, IRF7 was found to upregulate and activate STAT5B, a transcription factor of the JAK-STAT pathway frequently mutated in hematological malignancies. Together, these findings reveal a mechanism by which HTLV-1 hijacks a critical innate immune effector to sustain persistent infection and drive oncogenesis without activating antiviral IFN-I pathway.