HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.
HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA. chou-zen.giam@usuhs.edu.
Chou-Zen
CZ
Giam
Department of Microbiology and Molecular Cell Biology, The Leroy T. Canoles Jr Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA. semmesoj@evms.edu.
Oliver John
OJ
Semmes
D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D063646:Carcinogenesis; D016356:Gene Products, tax / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology* / Q000821:virology*; D012191:Retroviridae Proteins / Q000378:metabolism*; D017735:Virus Latency; D014779:Virus Replication
D050976:Basic-Leucine Zipper Transcription Factors; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; C514970:tax protein, Human T-lymphotrophic virus 1
DNA damage response; HTLV-1; K63-linked polyubiquitin; RNF8; UBC13; adult T-cell leukemia; genomic instability; latency and persistence; senescence