HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ

Abstract

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.

Keywords: DNA damage response; HTLV-1; K63-linked polyubiquitin; RNF8; UBC13; adult T-cell leukemia; genomic instability; latency and persistence; senescence.

Figure 1

Outcomes of HTLV-1 (Human T-cell lymphotropic virus type 1) infection. Proviral integration sites determine the levels of Tax/Rex expression in infected cells. During productive infection, high levels of Tax/Rex override HTLV-1 basic zipper protein (HBZ)-dependent inhibition to promote productive viral replication, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) hyperactivation, and cellular senescence. Approximately 98% of HeLa cells infected by HTLV-1 in culture become senescent [55]. When the levels of Tax/Rex are low, long terminal repeat (LTR) trans-activation, NF-κB activation, and senescence induction by Tax and viral mRNA nuclear export by Rex are inhibited by HBZ. As such, no viral structural proteins are expressed and the “latently” infected cells undergo mitotic expansion, likely propelled by HBZ and complemented by Tax that is expressed at subdued levels. The latent virus intermittently reactivates to initiate de novo HTLV-1 infection. The silencing of Tax and positive-sense viral mRNA expression are further selected by cytotoxic T lymphocyte (CTL) killing, resulting in an asymptomatic carrier state with little detectable serum levels of viral components.

Figure 2

Tax hijacks the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and E2 conjugating enzyme UBC13: Uev1A/Uev2 to activate transforming growth factor beta (TGFβ)-activated kinase 1 (TAK1), I kappa B kinase (IKK), canonical NF-κB and other signaling pathways. (A) Tax directly interacts with and stimulates RNF8 and Ubc13:Uev1A/2 to assemble long lysine 63-linked polyubiquitin (K63-pUb) chains, which then serve as the signaling scaffolds for K63-pUb-binding TAK1 and IKK to convene and become activated. As NF-κB essential modulator (NEMO) interacts weakly with K63-pUb chains, the direct interaction between Tax and NEMO may mediate IKK recruitment to and activation by TAK1. (B) The Tax-RNF8 signaling axis drives increased assembly of K63-linked polyubiquitin chains, which activate TAK1. TAK1, in turn, signals the activation of MKKs and IKK, and downstream p38 kinase, c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), and the canonical NF-κB pathway. The misappropriation and aberrant activation of RNF8 and the increased assembly of K63-linked polyubiquitin chains may sequester key mediators of DNA damage repair and cytokinesis to induce genomic instability in the forms of DNA double-strand breaks (DSBs) and chromosome aneuploidy.

Figure 3

A model for adult T-cell leukemia/lymphoma (ATL) development. Loss of senescence response and/or inhibition or down-regulation of NF-κB activation (cells marked with green nuclei) drives clonal expansion of HTLV-1-infected cells (each marked with a “+” sign). Some of these cells, presumably precancerous, continue to evolve, propelled by the genomic instability caused by either Tax or the loss of RNF8, eventually giving rise to ATL. The frequent genetic alterations detected in ATLs, such as activating point mutations in phospholipase Cγ1 (PLCG1), vav guanine nucleotide exchange factor 1 (VAV1), and protein kinase Cβ (PKCB), activating point mutations and deletions in caspase recruitment domain-containing protein 11 (CARD11), CTLA4/CD152–CD28, and inducible T-cell COStimulator (ICOS)/CD278–CD28 fusions, homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2), and chemokine (C-C motif) receptor 4 (CCR4), CCR7, and G protein-coupled receptor 183 (GPR183) truncations, are incorporated into this model to stimulate discussions and suggest future experiments.