Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL)

1. History of humans and Human T-cell Leukemia Virus Type 1 (HTLV-I)

HTLV-I is a member of the Deltaretroviruses, which include Human T-cell Leukemia Virus Type 2 (HTLV-II), bovine leukemia virus and simian T-cell leukemia virus (STLV). The latter two viruses also cause lymphoid malignancies in the host, similar to the case with HTLV-I. HTLV and STLV are thought to originate from common ancestors, and share molecular, virological and epidemiological features. Therefore, they have been designated primate T-cell leukemia viruses (PTLVs). Phylogenetical analyses have revealed that HTLV-Ic first diverged from simian leukemia virus around 50,000 ± 10,000 years ago, while the spread of PTLV-I in Africa is estimated to have occurred at least 27,300 ± 8,200 years ago. Subsequently, HTLV-Ia, which is the most common subtype in Japan, diverged from the African strain 12,300 ± 4,900 years ago [9]. Thus, these viruses have had a long history with humans after the interspecies transmission. In contrast, human immunodeficiency virus type 1 (HIV-1) is thought to originate from simian immunodeficiency virus in chimpanzees (SIV_CPZ) [10], and the interspecies transmission to humans is estimated to have occurred recently.

2. How does Human T-cell Leukemia Virus type 1 (HTLV-I) spread in humans?

There are approximately 10-20 million Human T-cell Leukemia Virus type 1 (HTLV-I) carriers in the world [11]. In particular, HTLV-I is endemic in Japan, parts of central Africa, the Caribbean basin and South America. In addition, epidemiological studies of HTLV-I have revealed high seroprevalence rates in Melanesia, Papua New Guinea and the Solomon islands, as well as among Australian aborigines [12]. In Japan, approximately 1.2 million individuals are estimated to be infected by Human T-cell Leukemia Virus type 1, and more than 800 cases of Adult T-cell Leukemia are diagnosed each year [13]. Moreover, this virus also causes the neurodegenerative disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [14,15]. The cumulative risks of ATL among HTLV-I carriers in Japan are estimated to be about 6.6% for men and 2.1% for women, indicating that most HTLV-I carriers remain asymptomatic throughout their lives [16].

3. How does Human T-cell Leukemia Virus Type 1 (HLVT-I) replicate and increase its copy number?

The Human T-cell Leukemia Virus Type 1 provirus has a similar structure to other retroviruses: a long terminal repeat (LTR) at both ends and internal sequences such as the gag, pol and env genes. A characteristic of HTLV-I is the presence of the pX region, which exists between env and the 3'-LTR. This region encodes several accessory genes, which include the tax, rex, p12, p21, p30, p13 and HBZ genes. Among these, the tax gene plays central roles in viral gene transcription, viral replication and the proliferation of HTLV-I-infected cells. Tax enhances viral gene transcription from the 5'-LTR via interaction with cyclic AMP responsive element binding protein (CREB). Tax also interacts with cellular factors and activates transcriptional pathways, such as NF-κB, AP-1 and SRF [8,17-20]. For example, activation of NF-κB induces the transcription of various cytokines and their receptor genes, as well as anti-apoptotic genes such as bcl-xL and survivin [21-23]. The activation of NF-κB has been demonstrated to be critical for tumorigenesis both in vitro and in vivo [24,25]. On the other hand, Tax variant without activation of NF-κB has also been reported to immortalize primary T-lymphocytes in vitro [26], suggesting that mechanisms of immortalization are complex. In addition to NF-κB, activation of other transcriptional pathways such as CREB by Tax should be implicated in the immortalization and leukemogenesis.

Tax also interferes with the functions of p53, p16 and MAD1 [27-30]. These interactions enable Human T-cell Leukemia Virus type 1-infected cells to escape from apoptosis, and also induce genetic instability. Although inactivation of p53 function by Tax is reported to be mediated by p300/CBP [27,28,31] or NF-κB activation [32], Tax can still repress p53's activity in spite of loss of p300/CBP binding or in cells lacking NF-κB activation [33], indicating the mechanism of p53 inactivation by Tax needs further investigation.

Although Tax promotes the proliferation of infected cells, it is also the major target of cytotoxic T-lymphocytes (CTLs) in vivo. Moreover, excess expression of Tax protein is considered to be harmful to infected cells. Therefore, Human T-cell Leukemia Virus Type 1 has redundant mechanisms to suppress Tax expression. Rex binds to Rex-responsive element (RxRE) in the U3 and R regions of the 3'-LTR, and enhances the transport of the unspliced gag/pol and the singly spliced env transcripts. By this mechanism, double-spliced tax/rex mRNA decreases, resulting in suppressed expression of Tax [34]. On the other hand, p30 binds to tax/rex transcripts, and retains them in the nucleus [35]. The HBZ gene is encoded by the complementary strand of HTLV-I, and contains a leucine zipper domain. HBZ directly interacts with c-Jun or JunB [36], or enhances their degradation [37], resulting in the suppression of Tax-mediated viral transcription from the LTR.

Transforming growth factor-β (TGF-β) is an inhibitory cytokine that plays important roles in development, the immune system and oncogenesis. Since TGF-β generally suppresses the growth of tumor cells, most tumor cells acquire escape mechanisms that inhibit TGF-β signaling, including mutations in its receptor and in the Smad molecules that transduce the signal from the receptor. Tax has also been reported to inhibit TGF-β signaling by binding to Smad2, 3 and 4 or CBP/p300 [38,39]. Inhibition of TGF-β signaling enables Human T-cell Leukemia Virus type 1-infected cells to escape TGF-β-mediated growth inhibition.

Adult T-cell Leukemia (ATL) cells have been reported to show remarkable chromosomal abnormalities [40], which should be implicated in the disease progression. Tax has been reported to interact with the checkpoint protein MAD1, which forms a complex with MAD2 and controls the mitotic checkpoint. This functional hindrance of MAD1 by Tax protein causes chromosomal instability, suggesting the involvement of this mechanism in oncogenesis [30]. Recently, Tax has been reported to interact with Cdc20 and activate Cdc20-associated anaphase-promoting complex, an E3 ubiquitin ligase that controls the metaphase-to-anaphase transition, thereby resulting in mitotic abnormalities [41].

In contrast to Human T-cell Leukemia Virus Type 1, Human T-cell Leukemia Virus Type 2 promotes the proliferation of CD8-positive T-lymphocytes in vivo. Although it was first discovered in a patient with variant hairy cell leukemia, HTLV-II is less likely to have oncogenic properties since there is no obvious association between HTLV-II infections and cancers. Regardless of the homology of their tax sequences, the oncogenic potential of Tax1 (HTLV-I Tax) is more prominent than that of Tax2 (HTLV-II Tax). The most striking difference is that Tax2 lacks the binding motif at C-terminal end to PDZ domain proteins, while Tax 1 retains it [42]. When the PDZ domain of Tax1 is added to Tax2, the latter acquires oncogenic properties in the rat fibroblast cell line Rat-1, indicating that this domain is responsible for the transforming activity of Human T-cell Leukemia Virus Type 1 [43].