Interferon dynamics in deltaretroviruses: why HTLV-1 evades, but BLV responds

Human T-cell leukemia virus type 1 (HTLV-1) and related deltaretroviruses are pathogenic retroviruses associated with severe diseases, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite advances in understanding their molecular biology, effective curative therapies remain limited. Interferons (IFNs), owing to their antiviral, antiproliferative, and immunomodulatory properties, have been widely investigated as therapeutic agents in this context. In vitro studies demonstrate that IFN-α, IFN-β, and IFN-Γ can suppress HTLV replication, inhibit viral protein expression, and reduce proliferation of infected cells. Clinical trials and case studies have further shown that IFN-α, particularly when combined with zidovudine (AZT) or arsenic trioxide, can reduce proviral load, downregulate viral oncoproteins such as Tax, and improve both hematological and neurological outcomes in ATL and HAM/TSP patients. However, the therapeutic efficacy varies, and resistance or incomplete responses highlight the limitations of IFN monotherapy. In bovine leukemia virus (BLV) infection, studies indicate that IFN-τ and IFN-Γ can suppress viral replication and modulate immune responses, suggesting their potential as preventive or therapeutic tools in cattle. Importantly, BLV has also been detected in human tissues, raising concerns about a possible zoonotic link with breast cancer, which underscores the broader public health significance of controlling BLV. This review summarizes the experimental and clinical evidence on IFN-based therapies for deltaretrovirus infection, discusses underlying mechanisms, and outlines the potential of combination regimens to improve patient outcomes.