|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
NEOPLASIA
From the National Cancer Institute, Basic Research
Laboratory, Bethesda, MD; and the National Heart, Lung, and Blood
Institute, Laboratory of Molecular Immunology, Bethesda, MD.
The p12I protein, encoded by the pX open reading frame
I of the human T-lymphotropic virus type 1 (HTLV-1), is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p12I contains 4 minimal proline-rich, src homology
3-binding motifs (PXXP), a characteristic commonly found in proteins
involved in signaling pathways, it has not been known whether
p12I has a role in modulating intracellular signaling
pathways. This study demonstrated that p12I binds to the
cytoplasmic domain of the interleukin-2 receptor (IL-2R) Human T-lymphotropic virus type 1 (HTLV-1) causes
adult T-cell leukemia/lymphoma (ATLL),1 and its genome
carries genetic information for the structural and enzymatic proteins,
the regulatory proteins Tax and Rex, and other open reading frames
(orfs) encoding small proteins with largely unknown
functions.2-5 HTLV-1 infects and immortalizes primary
human T cells in vitro, and after several months, these cells acquire
the ability to grow in the absence of interleukin-2
(IL-2).1 The switch to IL-2 independence correlates in
most cases with acquisition of a constitutive activation of the
Jak/signal transducers and activators of transcription (STAT) pathway6-8 and decreased expression of the src homology
2-containing tyrosine phosphatase 1 protein,9 which
regulates signaling from several hematopoietic surface
receptors.10 HTLV-1 also confers longevity on T cells in
vivo, since expansion of T cells with identical integrations for HTLV-1
can be found at several-year intervals in the same infected
individuals.11 These findings raise the question of how
CD4+ T cells carrying the HTLV-1 provirus can expand and
survive for a long time in vivo.
The HTLV-1 p12I protein, a hydrophobic protein resident in
the endoplasmic reticulum (ER) and Golgi58 that is encoded
by the 3' end orf I of the viral genome,12 forms
dimers,13 has weak oncogenic properties, and binds to the
p16 subunit of the vacuolar hydrogen adenosine diphosphatase
(H+ ATPase).14 Expression of p12I
in infected cells is suggested by the presence of transcripts in
cultured3,5,15 and ex vivo cells from individuals infected with HTLV-1.5 The orf I is likely expressed in vivo
because antibodies (Abs) and cytotoxic T lymphocytes to peptides from the orf I protein have been detected.16,17 Importantly,
ablation of the splice acceptor site for the singly spliced
p12I messenger RNA from a molecular clone of HTLV-1
impaired viral infectivity in a rabbit model in vivo.18
This may be partly related to the finding that p12I
interferes with major histocompatibility complex class I (MHC I)
heavy-chain trafficking and may facilitate escape of HTLV-1-infected cells from the host's immune surveillance.58
We previously reported that p12I also binds the IL-2
receptor (IL-2R) Because p12I interacts with the IL-2R Expression plasmids
DNA transfections, immunoprecipitations, Western blotting, and
immunofluorescence
Abs against the AU1 (Berkeley Antibody, Richmond, CA) and HA1 (12CA5;
Boehringer Mannheim, Indianapolis, IN) epitopes were used to
immunoprecipitate the wild-type p12I mutants. Monoclonal Ab
anti- Pseudotype virus production and concentration The 293T cells (2 × 106) were seeded on a 10-cm dish and transfected the following day with VSV-G (2 µg), pDNL6 (4 µg), and HR'CMV-Luc or HR'CMV p12I (4 µg) by using an Effectene reagent kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. Supernatant from 20 dishes was collected every 12 hours from 24 hours to 72 hours after transfection, cleared of cellular debris by centrifugation at 8000g for 10 minutes at room temperature, filtered through a 0.45 µm filter, and stored at 80°C. Pseudotype viruses were formed into pellets by
ultracentrifugation at 50 000g (28 000 rpm with a SW41
rotor) for 1.75 hours at 4°C. Virus was then resuspended in PBS by
means of a 4-hour incubation on ice, collected, divided into aliquots,
and stored at 80°C. HIV gag p24 was measured by using an
antigen capture assay (Coulter, Miami, FL). Primary peripheral blood
mononuclear cells (PBMCs) were infected by using comparable amounts of
viral particles for both HR'CMV-Luc and HR'CMV p12I.
Infectivity and expression were verified by immunofluorescence and
immunoprecipitation Western blot assays.
Primary T-cell infection and proliferation assay Mononuclear cells from peripheral blood of healthy volunteers were purified by Ficoll-Hypaque methods (Hyclone, Logan, UT), washed in PBS, and either used as such or after suboptimal stimulation obtained by phytohemagglutinin (PHA; 1 ng/mL) or CD3/CD28 (0.5 ng/mL) for 24 hours before infection with HR'CMV p12I or HR'CMV-Luc VSV pseudotyped viruses. Infected cells were plated in duplicate in a 96-well plate (3 × 104 cells/well) in 100 µL RPMI 1640 supplemented with 20% fetal-calf serum (FCS) in the absence or presence of 2.5, 5, or 10 U/mL IL-2 (Boehringer Mannheim). Cellular proliferation assays were done on days 2, 3, 4, and 6 after infection by using a Colorimetric Cell Proliferation Kit II (Roche Molecular, Indianapolis, IN) as described by the manufacturer. Spectrophotometric absorbance was measured with a mean filter at 492 nm and a reference filter at 690 nm. SDs were calculated from values obtained from 2 independent infections of each donor cell, and results were representative of 3 independent experiments done using cells from 3 human volunteers.Electrophoretic mobility shift assays PBMCs from healthy volunteers were purified with the Ficoll-Hypaque method, washed in PBS, activated with 5 µg/mL PHA for 3 days, washed again in PBS, and cultured for 5 days in RPMI 10% FCS and 10 U/mL IL-2. Lymphocytes were infected with HR'CMV p12I or HR'CMV-Luc pseudotype viruses. After 18 hours, PBMCs were washed twice in medium free of serum and IL-2 and deprived overnight of serum (0.1%) and stimulation with IL-2. The next day, infected PBMCs were divided into 6 batches of 2 × 106 cells and pulsed with 0.1, 1, 10, 100, or 1000 U/mL IL-2 for 10 minutes at 37°C. Unstimulated cells were used as controls for basal levels of STAT5 activation. Cells were collected by centrifugation and washed and lysed in 20 µL lysis buffer.22 Binding reactions were done with 2 µg protein extract, as previously reported,22 with an increase in incubation time from 30 minutes to 1 hour. STAT5 DNA binding activity was measured by using phosphorus 32 (32P)-labeled -casein  -interferon
activated sequence (GAS) elements. The DNA-protein complexes were
separated on prerun 5% native polyacrylamide gels in 0.5 × Tris
borate EDTA buffer at 200 V for 2 hours. Gels were dried and exposed to
x-ray film at 80°C. Gel-shift analysis using the -casein GAS
element was done as described previously.27 COS-7 cells
were transfected and pulsed with the selected amounts of IL-2, nuclear
extracts were made, and 10 µg of nuclear extracts were incubated with
20 000 cpm 32P-labeled -casein GAS element and run on
5% native polyacrylamide gels.
The 20-amino acid stretch of IL-2R chain, the CD4 and  chimeric molecules were
used.24 Both chimeric molecules coprecipitated with
p12I, indicating that neither the transmembrane nor the
extracellular domains of were the primary sites of p12I
interaction (data not shown). Mutants lacking different regions of the
-chain cytoplasmic domain were coexpressed with p12I,
and the cell lysate was divided in half and subjected to
immunoprecipitation and Western blot analysis with Ab to the receptor
(R&D Systems; goat antiserum against human IL-2R [RD]) and to
p12I (HA1) (Figure 1). The
 ST mutant lacking most of the cytoplasmic tail (267) failed to
bind p12I (Figure 1, bottom panel, lane 5). Although the
330 mutant also failed to bind p12I, the
350 mutant (lane 7) did bind, indicating that the region encompassing amino acids 330 to 350 of the receptor was required for
p12I binding (Figure 1, bottom panel, lanes 6 and 7). The
A mutant, which lacks amino acids 313 to 382, also did not bind
p12I, whereas the S mutant (267-322) did (Figure
1, bottom panels, lanes 13 and 14), further supporting this idea.
Because the p12I increases STAT5b DNA binding activity Because p12I binds the IL-2R chain in a region
involved in transduction of the IL-2 signal, we hypothesized that
p12I could modulate activation of the nuclear effector of
IL-2 signaling, STAT5. To investigate this hypothesis, the IL-2R
signaling pathway was reconstituted in a transient transfection
system27 in which IL-2R , c, Jak3, and
STAT5b proteins were coexpressed in the absence or presence of
p12I. In this experimental system, the phosphorylation and
DNA binding of STAT5 can be assessed before and after IL-2 triggering
of cells. COS-7 cells were pulsed with IL-2 for 20 minutes, and nuclear lysates were evaluated for the presence of activated STAT5b by measuring STAT5 binding to the -casein probe in electrophoretic mobility shift assays (EMSAs) as described previously.27 A
2- to 4-fold increase in the basal level of STAT5 binding to the -casein probe was observed in the presence of p12I
(Figure 2A, top panel, lanes 1 and 2).
Results with controls for equivalent expression of IL-2R and
p12I and the association of p12I with the IL-2R
chain are also shown in Figure 2A. Together, these findings suggest
that p12I increases STAT5 DNA binding in the absence of
IL-2 and that less IL-2 is required to promote STAT5b binding activity
in the presence of p12I.
p12I does not influence degradation of activated STAT5b IL-2-induced STAT5 activation is tightly regulated by dephosphorylation and protein degradation.28 To investigate whether the increase in p12I-induced STAT5 activation resulted from a delay in its degradation, we studied the decay of STAT5 binding activity after IL-2 pulsing and removal of the ligand. Higher levels of STAT5 binding activity were detected in the presence of p12I at all time points after the IL-2 washout (Figure 2B). However, the rate of decay of the STAT5 binding activity did not appear to be affected by p12I, since the amount of STAT5b binding to the-casein probe was reduced by about 50% at 80 minutes (Figure 2C). Thus, p12I does not appear to increase
IL-2R signaling by delaying STAT5 inactivation or degradation.
p12I binding to the IL-2R -casein promoter luciferase reporter gene was used to measure STAT5b transcriptional activation in the presence of p12I.
We found that p12I increased STAT5b transcriptional
activity by approximately 2-fold to 3-fold (Figure
3A); this increase was also evident in
the presence of increasing amounts of IL-2 (Figure 3B). Approximately
10-fold less IL-2 was required to obtain an equivalent level of STAT5b transcriptional activity, as indicated, for example, by the fact that
luciferase activity in the presence of p12I with 1 nM IL-2
was equivalent to that obtained in the absence of p12I with
10 nM IL-2 (Figure 3B).
The increase in STAT5b transcriptional activity induced by
p12I required the presence of all components of the IL-2R
pathway, since the absence of p12I increases STAT5 phosphorylation and DNA binding in primary human PBMCs HTLV-1 infects and transforms human primary PBMCs both in vivo and in vitro. Therefore, we investigated whether p12I would increase STAT5 activation in its natural target-cell population. An HIV-1-based retroviral vector expressing p12I was constructed (HR'CMV p12I). Expression of HA1-tagged p12I was assessed first in transfected 293T cells by Western blotting, and the characteristic doublet of p12I was readily detected (Figure 4A). Transduction of HR'CMV p12I in primary human PBMCs was properly localized in the ER-Golgi compartment, as demonstrated by confocal immunofluorescence (Figure 4B).
To assess the effect of p12I on PBMCs, peripheral blood
lymphocytes from healthy volunteers were infected with pseudotype
viruses carrying p12I or the luciferase genes. After 18 hours, PBMCs were deprived of serum and IL-2 to lower the STAT5 basal
level of DNA binding activity. Cells were then pulsed for 10 minutes
with various concentrations of IL-2, and STAT5 phosphorylation and
activation was assessed by either gel-shift assay or Western blot using
Ab to phosphorylated STAT5. The expected DNA-protein complex in nuclear
extracts of cells pulsed with IL-2 was readily observed by using the
p12I decreases the IL-2 requirement for T-cell proliferation An expected consequence of an increased basal level of STAT5 activation is that cell proliferation may occur with a lower concentration of exogenous IL-2. To investigate this hypothesis, PBMCs from healthy volunteers were isolated, washed in PBS, and either used as such or after suboptimal stimulation with either PHA (1 ng/mL) or CD3/CD28 (0.5 ng/mL) for 24 hours before infection with HR'CMV p12I or HR'CMV-Luc pseudotype viruses. Infected cells were then divided into 4 aliquots and plated in duplicate in 96-well plates in the absence or presence of 2.5, 5, and 10 or 100 U IL-2. Cellular proliferation was monitored as described.30 The p12I-transduced PBMCs stimulated in suboptimal conditions proliferated faster than the Luc-transduced PBMC control (Figure 5) and, although this effect was evident with 2.5 U and 5 U IL-2 (Figure 5D-E), it was lost at higher concentrations10 of the ligand (Figure 5E). Furthermore, this effect was evident only within the first few days after infection, it became undetectable 4 days after infection (Figure 5F), and it was not observed at all in unstimulated resting PBMCs (Figure 5A-C). Other studies suggested that p12I may affect HTLV-1 infectivity by promoting activation of quiescent primary T lymphocytes.31 Our results, obtained from experiments with samples from 3 different donors, do not seem to support this conclusion, since p12I did not stimulate T cells to proliferate in the absence of an exogenous activating signal. Together, these data suggest that p12I expression alone is not sufficient to activate T cells but that it enables T cells, activated in suboptimal conditions, to proliferate even in the presence of a low level of IL-2.
HTLV-1 has persisted in nonhuman and human primates for thousands
of years, as shown by the finding of proviral DNA in Andean mummies.32 HTLV-1 virions, in contrast to HIV-1 virions,
are poorly infectious in vitro, and HTLV-1 is thought to be transmitted efficiently mainly through cell-to-cell contact.1
Therefore, maintenance of a large pool of long-lasting infected T cells
carrying the provirus in infected individuals11 has likely
been instrumental in preventing extinction of HTLV-1. However, the
expansion of infected T cells does not occur without risk. In fact, in
1% to 2% of individuals infected with HTLV-1, ATLL, a fatal clonal
disease, develops, presumably by means of accidental accumulation of
somatic mutations of genes that regulate T-cell growth.4
The ways in which HTLV-1 immortalizes T cells in vitro likely mirror
the mechanisms used by the virus in vivo. In vitro, the viral
transactivator Tax overrides normal mechanisms for controlling cell
growth by affecting the activity of regulators of cell-cycle
progression, such as p53,33-35
p16INK4A,36-38 the Rb protein,39
and MAD1,40 and by either suppressing expression of the
cell-cycle regulators c-Myb41 and B-Myb42 or
increasing expression of antiapoptotic proteins, including Bcl-X However, although Tax is important in preventing T-cell apoptosis and cell-cycle arrest, its immunogenicity in vivo47 may interfere with the ability of infected cells to survive immune recognition. The HTLV-1 p12I protein may play a crucial role in this regard. First, the ability of p12I to target the MHC I for degradation58 may markedly decrease the density of the MHC I/viral-peptide complexes (including Tax peptides) on the cell surface and render the infected cells invisible to recognition by cytotoxic T lymphocytes. Second, as demonstrated in this study, the ability of p12I to increase the basal level of STAT5 activation and T-cell responsiveness to IL-2, coupled with the costimulatory effect of Tax, may ultimately result in a limited burst of virus as well as limited replication of HTLV-1-infected T cells. Both the Tax costimulatory effect and the increased STAT5 activation induced by p12I appear to depend on antigen or mitogen stimulation, suggesting that cell-cycle entry of HTLV-1-infected T cells may be promoted in the presence of antigen stimulation in the microenvironment. In support of this hypothesis, epidemiologic studies have indicated that patients with concomitant Strongyloides stercoralis infection have a higher frequency of ATLL.48-51 Interestingly, HTLV-1 and HIV-1 have independently evolved 2 proteins (p12I and Nef) with similar cellular targets. Both p12I and Nef target subunits (although different) of the vacuolar H+ATPase14,52; p12I interferes with trafficking of MHC I heavy chain to the cell surface,58 whereas Nef down-regulates the MHC I that has already reached the cell surface, and both proteins increase IL-2 responsiveness (though by different mechanisms).9,53-55 In addition, ablation of Nef and p12I from molecular clones of simian immunodeficiency virus and HTLV-1, respectively, results in a similar phenotype, ie, their absence impairs viral infectivity in vivo, but their presence is not essential for viral infectivity or replication in tissue culture.56,57 Thus, the 3' region of both human retroviruses encodes proteins (p12I and Nef) that help to preserve life-long infection of humans while increasing the likelihood of viral transmission.
We thank Steven Snodgrass for editorial assistance.
Submitted October 3, 2000; accepted March 28, 2001.
C.N. and J.C.M. contributed equally.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Genoveffa Franchini, National Cancer Institute, Basic Research Laboratory, 41/D804, Bethesda, MD 20892; e-mail: veffa{at}helix.nih.gov.
1. Gallo RC. The first human retrovirus. Sci Am. 1986;255:88-98[Medline] [Order article via Infotrieve].
2.
Berneman ZN, Gartenhaus RB, Reitz MS Jr, et al.
Expression of alternatively spliced human T-lymphotropic virus type I (HTLV-I) pX mRNA in infected cell lines and in primary uncultured cells from patients with adult T-cell leukemia/lymphoma and healthy carriers.
Proc Natl Acad Sci U S A.
1992;89:3005-3009
3.
Ciminale V, Pavlakis GN, Derse D, Cunningham CP, Felber BK.
Complex splicing in the human T-cell leukemia virus (HTLV) family of retroviruses: novel mRNAs and proteins produced by HTLV-I.
J Virol.
1992;66:1737-1745
4.
Franchini G.
Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection.
Blood.
1995;86:3619-3639
5.
Koralnik I, Gessain A, Klotman ME, Lo Monico A, Berneman ZN, Franchini G.
Protein isoforms encoded by the pX region of the human T-cell leukemia/lymphotropic virus type I.
Proc Natl Acad Sci U S A.
1992;89:8813-8817
6.
Migone TS, Lin JX, Cereseto A, et al.
Constitutively activated JAK-STAT pathway in T-cells transformed with HTLV-I.
Science.
1995;269:79-81
7.
Mulloy JC, Migone T-S, Ross TM, et al.
Human and simian T-cell leukemia viruses type 2 (HTLV-2 and STLV-2pan-p) transform T-cells independently of Jak/STAT activation.
J Virol.
1998;72:4408-4412 8. Xu X, Kang SH, Heidenrich O, Okerholm M, O'Shea JJ, Nerenberg MI. Constitutive activation of different Jak tyrosine kinases in human T-cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells. J Clin Invest. 1995;96:1548-1555.
9.
Migone TS, Cacalano NA, Taylor N, Yi T, Waldmann TA, Johnston JA.
Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells.
Proc Natl Acad Sci U S A.
1998;95:3845-3850 10. Leonard WJ, O'Shea JJ. JAKs and STATs: biological implications. Annu Rev Immunol. 1998;16:293-322[CrossRef][Medline] [Order article via Infotrieve]. 11. Wattel E, Vartanian JP, Pannetier C, Wain-Hobson S. Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy. J Virol. 1995;69:2863-2868[Abstract].
12.
Koralnik IJ, Fullen J, Franchini G.
The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments.
J Virol.
1993;67:2360-2366
13.
Trovato R, Mulloy JC, Johnson JM, Takemoto S, de Oliveira MP, Franchini G.
A lysine-to-arginine change found in natural alleles of the HTLV-I p12I protein greatly influences its stability.
J Virol.
1999;73:6460-6467
14.
Franchini G, Mulloy JC, Koralnik IJ, et al.
The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase.
J Virol.
1993;67:7701-7704 15. Koralnik I, Lemp JF Jr, Gallo RC, Franchini G. In vitro infection of human macrophages by human T-cell leukemia/lymphotropic virus type I (HTLV-I). AIDS Res Hum Retroviruses. 1992;8:1845-1849[Medline] [Order article via Infotrieve]. 16. Dekaban GA, Peters AA, Mulloy JC, et al. The HTLV-I orf I protein is recognized by serum antibodies from naturally infected humans and experimentally infected rabbits. Virology. 2000;274:86-93[CrossRef][Medline] [Order article via Infotrieve].
17.
Pique C, Ureta-Vidal A, Gessain A, et al.
Evidence for the chronic in vivo production of human T cell leukemia virus type I Rof and Tof proteins from cytotoxic T lymphocytes directed against viral peptides.
J Exp Med.
2000;191:567-572
18.
Collins ND, Newbound GC, Albrecht B, Beard JL, Ratner L, Lairmore MD.
Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo.
Blood.
1998;91:4701-4707
19.
Mulloy JC, Crowley RW, Fullen J, Leonard WJ, Franchini G.
The human T-cell leukemia/lymphotropic virus type I p12I protein binds the interleukin-2 receptor 20. Smith KA, Jacobson EL, Emert R, et al. Restoration of immunity with interleukin-2 therapy. AIDS Read. 1999;9:563-572[Medline] [Order article via Infotrieve]. 21. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene. 2000;19:2474-2488[CrossRef][Medline] [Order article via Infotrieve].
22.
Takemoto S, Mulloy JC, Cereseto A, et al.
Proliferation of adult T-cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins.
Proc Natl Acad Sci U S A.
1997;94:13897-13902 23. Bromberg J, Darnell JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19:2468-2473[CrossRef][Medline] [Order article via Infotrieve].
24.
Nakamura Y, Russell SM, Mess SA, et al.
Heterodimerization of the IL-2 receptor 25. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263-267[Abstract]. 26. Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973;52:456-460[CrossRef][Medline] [Order article via Infotrieve].
27.
Zhu M-H, Berry JA, Russell SM, Leonard WJ.
Delineation of the regions of interleukin-2 (IL-2) receptor
28.
Yu CL, Burakoff SJ.
Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation.
J Biol Chem.
1997;272:14017-14020
29.
Hatakeyama M, Mori H, Doi T, Taniguchi T.
A restricted cytoplasmic region of IL-2 receptor
30.
Scudiero DA, Shoemaker RH, Paull KD, et al.
Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines.
Cancer Res.
1988;48:4827-4833
31.
Albrecht B, Collins ND, Burniston MT, et al.
Human T-lymphotropic virus type 1 open reading frame I p12(I) is required for efficient viral infectivity in primary lymphocytes.
J Virol.
2000;74:9828-9835 32. Li HC, Fujiyoshi T, Lou H, et al. The presence of ancient human T-cell lymphotropic virus type I provirus DNA in an Andean mummy. Nat Med. 1999;5:1428-1432[CrossRef][Medline] [Order article via Infotrieve].
33.
Mulloy JC, Kislyakova T, Cereseto A, et al.
Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain.
J Virol.
1998;72:8852-8860
34.
Pise-Masison CA, Radonovich M, Sakaguchi K, Appella E, Brady JN.
Phosphorylation of p53: a novel pathway for p53 inactivation in human T-cell lymphotropic virus type 1-transformed cells.
J Virol.
1998;72:6348-6355
35.
Pise-Masison CA, Choi K-S, Radonovich M, Dittmer J, Kim S-J, Brady JN.
Inhibition of p53 transactivation function by the human T-cell lymphotropic virus type 1 Tax protein.
J Virol.
1998;72:1165-1170 36. Franchini G, Cereseto A, Tryniszewska E, et al. Telomerase activation, rearrangement, and inhibition of cell-cycle inhibitors in human T-cells immortalized or transformed by HTLV-I. In: Semmes OJ,Hammarskjold M-L, eds. Molecular Pathogenesis of HTLV-I: A Current Perspective. Arlington, VA: ABI Professional Publications; 1999:59-70. 37. Low KG, Dorner LF, Fernando DB, Grossman J, Jeang K-T, Comb MJ. Human T-cell leukemia virus type 1 tax releases cell cycle arrest induced by p16INK4a. J Virol. 1997;71:1956-1962[Abstract]. 38. Suzuki T, Kitao S, Matsushime H, Yoshida M. HTLV-I Tax protein interacts with cyclin-dependent kinase inhibitor p16ink4a and counteracts its inhibitory activity towards CDK4. EMBO J. 1996;15:1607-1614[Medline] [Order article via Infotrieve].
39.
Neuveut C, Low KG, Maldarelli F, et al.
Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb.
Mol Cell Biol.
1998;18:3620-3632 40. Jin D-Y, Spencer F, Jeang K-T. Human T-cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998;93:1-20[CrossRef][Medline] [Order article via Infotrieve]. 41. Nicot C, Mahieux R, Opavsky R, et al. HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300. Oncogene. 2000;19:2155-2164[CrossRef][Medline] [Order article via Infotrieve]. 42. Nicot C, Opavsky R, Mahieux R, et al. Tax oncoprotein trans-represses the endogenous B-myb promoter activity in human T cells. AIDS Res Hum Retroviruses. 2000;16:1629-1632[CrossRef][Medline] [Order article via Infotrieve].
43.
Nicot C, Mahieux R, Takemoto S, Franchini G.
Bcl-XL is up-regulated by HTLV type I and type II in vitro and in ex vivo ATLL samples.
Blood.
2000;96:275-281
44.
Good L, Maggirwar SB, Harhaj EW, Sun S-C.
Constitutive dephosphorylation and activation of a member of the nuclear factor of activated T cells, NF-AT1, in Tax-expressing and type I human T-cell leukemia virus-infected human T cells.
J Biol Chem.
1997;272:1425-1428 45. Good L, Maggirwar SB, Sun S-C. Activation of the IL-2 gene promoter by HTLV-I Tax involves induction of NF-AT complexes bound to the CD28-responsive element. EMBO J. 1996;15:3744-3750[Medline] [Order article via Infotrieve].
46.
Ballard DW, Dohnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC.
HTLV-I tax induces cellular proteins that activate the 47. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990;348:245-248[CrossRef][Medline] [Order article via Infotrieve]. 48. Agape P, Copin MC, Cavrois M, et al. Implication of HTLV-I infection, strongyloidiasis, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphomas in an endemic area (Martinique, French West Indies). J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:394-402[Medline] [Order article via Infotrieve]. 49. Arakaki T, Asato R, Ikeshiro T, Sakiyama K, Iwanaga M. Is the prevalence of HTLV-1 infection higher in Strongyloides carriers than in non-carriers? Trop Med Parasitol. 1992;43:199-200[Medline] [Order article via Infotrieve]. 50. Arakaki T, Kohakura M, Asato R, Ikeshiro T, Nakamura S, Iwanaga M. Epidemiological aspects of Strongyloides stercoralis infection in Okinawa, Japan. J Trop Med Hyg. 1992;95:210-213[Medline] [Order article via Infotrieve]. 51. Atkins NS, Lindo JF, Lee MG, Hanchard B, Robinson RD, Bundy DA. Immunomodulatory effects of concurrent HTLV-I infection in strongyloidiasis. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:188-190[Medline] [Order article via Infotrieve]. 52. Lu X, Yu H, Liu S, Brodsky F, Peterlin B. Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. Immunity. 1998;8:647-656[CrossRef][Medline] [Order article via Infotrieve].
53.
Manninen A, Herma Renkema G, Saksela K.
Synergistic activation of NFAT by HIV-1 nef and the Ras/MAPK pathway.
J Biol Chem.
2000;275:16513-16517
54.
Schrager JA, Marsh JW.
HIV-1 Nef increases T cell activation in a stimulus-dependent manner.
Proc Natl Acad Sci U S A.
1999;96:8167-8172
55.
Wang JK, Kiyokawa E, Verdin E, Trono D.
The Nef protein of HIV-1 associates with rafts and primes T cells for activation.
Proc Natl Acad Sci U S A.
2000;97:394-399 56. Derse D, Mikovits J, Ruscetti F. X-I and X-II open reading frames of HTLV-I are not required for virus replication or for immortalization of primary T-cells in vitro. Virology. 1997;237:123-128[CrossRef][Medline] [Order article via Infotrieve].
57.
Robek MD, Wong F-H, Ratner L.
Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are dispensable for the immortalization of primary lymphocytes.
J Virol.
1998;72:4458-4462 58. Johnson JM, Nicot C, Fullen J, et al. Free major histocompatibility complex class I heavy chain is preferentially targeted for degradation by human T-cell leukemia/lymphotropic virus type 1 p12I protein. J Virol. In press. 59. Waldmann TA, Dubois S, Tagaya Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity. 2001;14:105-110[Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  J. M. Taylor, M. Brown, M. Nejmeddine, K. J. Kim, L. Ratner, M. Lairmore, and C. Nicot Novel Role for Interleukin-2 Receptor-Jak Signaling in Retrovirus Transmission J. Virol., November 15, 2009; 83(22): 11467 - 11476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Fukumoto, V. Andresen, I. Bialuk, V. Cecchinato, J.-C. Walser, V. W. Valeri, J. M. Nauroth, A. Gessain, C. Nicot, and G. Franchini In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein Blood, April 16, 2009; 113(16): 3726 - 3734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Li, M. Kesic, H. Yin, L. Yu, and P. L. Green Kinetic Analysis of Human T-Cell Leukemia Virus Type 1 Gene Expression in Cell Culture and Infected Animals J. Virol., April 15, 2009; 83(8): 3788 - 3797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Grant, U. Oh, K. Yao, Y. Yamano, and S. Jacobson Dysregulation of TGF-{beta} signaling and regulatory and effector T-cell function in virus-induced neuroinflammatory disease Blood, June 15, 2008; 111(12): 5601 - 5609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G P Taylor Molecular aspects of HTLV-I infection and adult T-cell leukaemia/lymphoma J. Clin. Pathol., December 1, 2007; 60(12): 1392 - 1396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fukumoto, M. Dundr, C. Nicot, A. Adams, V. W. Valeri, L. E. Samelson, and G. Franchini Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1 J. Virol., September 1, 2007; 81(17): 9088 - 9099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Asquith, Y. Zhang, A. J. Mosley, C. M. de Lara, D. L. Wallace, A. Worth, L. Kaftantzi, K. Meekings, G. E. Griffin, Y. Tanaka, et al. In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection PNAS, May 8, 2007; 104(19): 8035 - 8040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Waldele, K. Silbermann, G. Schneider, T. Ruckes, B. R. Cullen, and R. Grassmann Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes Blood, June 1, 2006; 107(11): 4491 - 4499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-j. Kim, A. M. Nair, S. Fernandez, L. Mathes, and M. D. Lairmore Enhancement of LFA-1-Mediated T Cell Adhesion by Human T Lymphotropic Virus Type 1 p12I1 J. Immunol., May 1, 2006; 176(9): 5463 - 5470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Sinha-Datta, I. Horikawa, E. Michishita, A. Datta, J. C. Sigler-Nicot, M. Brown, M. Kazanji, J. C. Barrett, and C. Nicot Transcriptional activation of hTERT through the NF-{kappa}B pathway in HTLV-I-transformed cells Blood, October 15, 2004; 104(8): 2523 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Waldele, G. Schneider, T. Ruckes, and R. Grassmann Interleukin-13 Overexpression by Tax Transactivation: a Potential Autocrine Stimulus in Human T-Cell Leukemia Virus-Infected Lymphocytes J. Virol., June 15, 2004; 78(12): 6081 - 6090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Silverman, A. J. Phipps, A. Montgomery, L. Ratner, and M. D. Lairmore Human T-Cell Lymphotropic Virus Type 1 Open Reading Frame II-Encoded p30II Is Required for In Vivo Replication: Evidence of In Vivo Reversion J. Virol., April 15, 2004; 78(8): 3837 - 3845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ding, S.-J. Kim, A. M. Nair, B. Michael, K. Boris-Lawrie, A. Tripp, G. Feuer, and M. D. Lairmore Human T-Cell Lymphotropic Virus Type 1 p12I Enhances Interleukin-2 Production during T-Cell Activation J. Virol., October 15, 2003; 77(20): 11027 - 11039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ding, B. Albrecht, R. E. Kelley, N. Muthusamy, S.-J. Kim, R. A. Altschuld, and M. D. Lairmore Human T-Cell Lymphotropic Virus Type 1 p12I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells J. Virol., September 11, 2002; 76(20): 10374 - 10382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Albrecht and M. D. Lairmore Critical Role of Human T-Lymphotropic Virus Type 1 Accessory Proteins in Viral Replication and Pathogenesis Microbiol. Mol. Biol. Rev., September 1, 2002; 66(3): 396 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Pise-Masison, M. Radonovich, R. Mahieux, P. Chatterjee, C. Whiteford, J. Duvall, C. Guillerm, A. Gessain, and J. N. Brady Transcription Profile of Cells Infected with Human T-cell Leukemia Virus Type I Compared with Activated Lymphocytes Cancer Res., June 1, 2002; 62(12): 3562 - 3571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Albrecht, C. D. D'Souza, W. Ding, S. Tridandapani, K. M. Coggeshall, and M. D. Lairmore Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12I J. Virol., March 7, 2002; 76(7): 3493 - 3501. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
B element in the IL-2 receptor