Stratagems of HTLV-1 for persistent infection and the resultant oncogenesis: Immune evasion and clonal expansion

Abstract

Adult T-cell leukemia-lymphoma (ATL) is one of the most severe malignant T-cell leukemia/lymphomas induced by human T-cell leukemia virus type I (HTLV-1). HTLV-1 persists in the host through stratagems of proliferating infected cells and evading host immunity. HTLV-1 encodes two viral oncogenes, tax and HTLV-1 bZIP factor (HBZ), which are related with protection from cell death and promotion of cell proliferation. In addition, HBZ and the somatic mutations in host genes, such as C-C chemokine receptor 4 (CCR4) and CIC, convert HTLV-1–infected cells into regulatory T (Treg)-like cells, leading to evasion of host immunity. A recent study demonstrated the key mechanisms for clonal expansion of HTLV-1–infected cells; the activation of the transforming growth factor (TGF)-β signaling pathway by HBZ not only converts HTLV-1–infected cells into a Treg-like cells through Foxp3 expression, but also contributes to the proliferation of HTLV-1–infected cells themselves. Due to the longevity induced by HTLV-1 infection, somatic mutations and epigenetic aberrations are accumulated in infected clones, contributing to the oncogenesis of ATL. Collectively, the long-term survival of infected cells enabled by the HTLV-1’s stratagems for persistent infection ultimately leads to ATL oncogenesis via the accumulation of genetic/epigenetic abnormalities.