Exploitation of CREB signaling by HTLV-1 and BLV: A central axis in viral persistence and leukemogenesis.

Deltaretroviruses, including Human T-cell Leukemia Virus type 1 (HTLV-1) and Bovine Leukemia Virus (BLV), are oncogenic pathogens that exploit host transcriptional machinery to establish persistence and drive malignant transformation. Central to this process is the cAMP response element-binding protein (CREB), a transcription factor that regulates cell survival, proliferation, and differentiation. Viral proteins, such as Tax and HBZ, directly interact with CREB and its cofactors (CBP/p300, TORC2), enabling the robust activation of viral long terminal repeats (LTRs) and the dysregulation of host gene expression, including key regulators of apoptosis and the cell cycle. CREB phosphorylation and complex assembly with Tax and cofactors are critical steps in sustaining viral replication, anti-apoptotic signaling, and oncogenesis. Comparative studies highlight conserved roles of CREB in both HTLV-1 and BLV, where it not only mediates viral transcription but also contributes to immune evasion, genomic instability, and malignant progression. Epigenetic modulation and cellular factors, such as c-Maf and MEF-2, further refine CREB-dependent transcriptional outcomes, underscoring the intricate interplay between virus and host. Importantly, clinical data from patients with Adult T-cell Leukemia/Lymphoma (ATLL) show CREB overexpression and a correlation with viral gene expression, reinforcing its role in disease progression. Collectively, these findings establish CREB as a central hub in deltaretrovirus biology and pathogenesis. Targeting CREB signaling may therefore represent a promising therapeutic strategy for controlling both HTLV-1 and BLV-associated malignancies. This review integrates current knowledge of CREB's role in deltaretrovirus infection and highlights its potential as a therapeutic target for future antiviral and anticancer interventions.