Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes

Abstract

IntroductionThe human T cell leukemia virus type 1 (HTLV-1) infection is causally linked with the development of a severe and fatal lymphoproliferative disorder of CD4 ϩ T cells, the adult T cell leukemia (ATL), and of the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). [1][2][3][4] Both diseases develop only after prolonged viral persistence. The HTLV-1 infection seems to stimulate growth and survival of the T-lymphocytes in carriers, since they expand to detectable clones, which can persist over many years even in nonleukemic individuals. 5,6 This notion is corroborated by the virus's capacity to stimulate permanent T-lymphocyte growth in vitro, resulting in T-cell immortalization. Hence, it is highly probable that viral gene functions are not only involved in immortalization of T-cell cultures, but also cause the clonal expansion of patient lymphocytes. Such growth-stimulating functions provide means to replicate the (pro-) viral genome without producing virus particles.Being a prototypic delta-retrovirus, HTLV-1 encodes the regulatory nonstructural proteins Tax and Rex, which are essential for viral replication, 7 and the accessory proteins p12, p30, and p13. While Rex acts at a posttranscriptional level 8,9 to control the expression of the structural proteins, Tax strongly enhances viral gene expression by transactivating the HTLV-1 long-terminalrepeat promoter. 10 Although the accessory proteins are important for viral infectivity and replication by influencing cellular signaling and gene expression, [11][12][13][14][15][16] p12, p13, and p30 are dispensable for lymphocyte immortalization. 17,18 Biochemically, Tax can stimulate transcription by affecting various pathways. Nuclear factor-B (NF-B) is activated by binding and stimulating IKK␥, a component of the inhibitor of kappa B kinase. 19 Transactivation of various cellular promoters is mediated by binding to the transcriptional activators CREB and SRF, and to the coactivators p300/CBP. 10,20 Tax also induces activator protein-1 (AP-1), a transcription factor complex composed of members of the Fos/Jun family, 21,22 and stimulates transcription via nuclear factor of activated T-cell (NF-AT) elements. [23][24][25] Tax confers the transforming properties on the virus. It is capable of immortalizing T cells 26,27 and is leukemogenic in transgenic mice. 28 It interferes with normal cell-cycle control by dysregulating control checkpoints. 29 In particular, Tax is capable of stimulating the G 1 phase by binding to and activating cyclindependent kinase holoenzymes; it also inhibits DNA repair and induces aneuploidy. [30][31][32][33][34][35] Importantly, it interferes with tumor suppressor functions; for instance, it inactivates p53. 36,37 Moreover, Tax can stimulate or repress the expression of cellular proteins involved in cell survival and proliferation. Among those are proto-oncogenes (c-FOS, EGR1), cytokines, and cytokine receptors, 20,25,38 as well as cell-cycle regulators (p21 WAF1/CIP1 ). Taxmediated modulati...

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

“…45 Of note, this HTLV-1-stimulated, NF-kB-mediated abnormal expression of c-IAP2 contributes to the suppression of programmed cell death and supports the increased survival of HTLV-1-transformed lymphocytes. 45 This was demonstrated by RNA interference-mediated gene silencing of c-IAP2, which resulted in increased caspase activation and apoptosis along with reduced cell growth. 45 The prognostic significance of XIAP in acute myeloid leukemia (AML) has been controversially discussed.…”

“…In human T-cell leukemia virus type 1 (HTLV-1)-transformed adult T-cell leukemia, the viral oncoprotein Tax that is encoded by HTLV-1 aberrantly stimulates activation of the transcription factor NF-kB. 45 This in turn causes increased transcription of c-IAP2 as a prototype NF-kB target gene, leading to elevated protein expression of c-IAP2, a typical feature of adult T-cell leukemia. 45 Of note, this HTLV-1-stimulated, NF-kB-mediated abnormal expression of c-IAP2 contributes to the suppression of programmed cell death and supports the increased survival of HTLV-1-transformed lymphocytes.…”

“…45 This in turn causes increased transcription of c-IAP2 as a prototype NF-kB target gene, leading to elevated protein expression of c-IAP2, a typical feature of adult T-cell leukemia. 45 Of note, this HTLV-1-stimulated, NF-kB-mediated abnormal expression of c-IAP2 contributes to the suppression of programmed cell death and supports the increased survival of HTLV-1-transformed lymphocytes. 45 This was demonstrated by RNA interference-mediated gene silencing of c-IAP2, which resulted in increased caspase activation and apoptosis along with reduced cell growth.…”

“…45 This was demonstrated by RNA interference-mediated gene silencing of c-IAP2, which resulted in increased caspase activation and apoptosis along with reduced cell growth. 45 The prognostic significance of XIAP in acute myeloid leukemia (AML) has been controversially discussed. One study reported that AML patients with lower XIAP protein levels exhibited a significantly longer survival and also showed a tendency toward longer duration of remission compared with patients with higher XIAP protein levels.…”

Strong induction of 4-1BB, a growth and survival promoting costimulatory receptor, in HTLV-1–infected cultured and patients' T cells by the viral Tax oncoprotein

“…For example, RNAi-mediated knockdown of expression of the antiapoptotic protein HIAP1/CIAP2 induces apoptosis in HTLV-1-transformed T-cell lines. 35 The persistence of HTLV-1 in T-cell clones detectable over many years suggested that proteins mediating survival and growth of long-lived T cells could be crucial for HTLV-1 persistence and, thus, be potential targets of its oncoprotein Tax. Such properties are characteristic of the costimulatory receptor subgroup of the tumor necrosis factor receptor (TNFR) superfamily.…”