Susceptibility of Human T Cell Leukemia Virus Type I to Nucleoside Reverse Transcriptase Inhibitors

Hill, S. A.; Lloyd, Patricia A.; McDonald, Shannon L.; Wykoff, Jennifer; Derse, David

doi:10.1086/376531

Cited by 47 publications

(37 citation statements)

References 18 publications

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“…However, another study reported that lamivudine had no definite effect on proviral load (34). In this study, administering tenofovir to block the spread of infection to new cells did not influence the proviral load in hu-PBMC-NOG mice, even though tenofovir has been reported to be more efficient in inhibiting HTLV-1 replication than lamivudine (20). Taken together, these results suggest that clonal proliferation contributes to the increase of HTLV-1-infected cells more than internal contagion even early in HTLV-1 infection.…”

Section: Discussioncontrasting

confidence: 51%

“…A previous in vitro study reported that AZT was able to inhibit new HTLV-1 infection of human lymphocytes (37). In addition, it has been reported that tenofovir efficiently inhibited the reverse transcriptase activity of HTLV-1 (20). In order to assess whether a preventive antiretroviral treatment would prove useful in cases of accidental HTLV-1 exposure, we treated hu-PBMC-NOG mice with two reverse transcriptase inhibitors, AZT and tenofovir.…”

Section: Significant Increase In the Memory Cd4 ؉ T-cell Population Amentioning

confidence: 99%

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De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

Miyazato¹,

Yasunaga²,

Taniguchi³

et al. 2006

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia, a disease that is triggered after a long latency period. HTLV-1 is known to spread through cell-to-cell contact. In an attempt to study the events in early stages of HTLV-1 infection, we inoculated uninfected human peripheral blood mononuclear cells and the HTLV-1-producing cell line MT-2 into NOD-SCID, common ␥-chain knockout mice (human PBMC-NOG mice). HTLV-1 infection was confirmed with the detection of proviral DNA in recovered samples. Both CD4؉ and CD8 ؉ T cells were found to harbor the provirus, although the latter population harbored provirus to a lesser extent. Proviral loads increased with time, and inverse PCR analysis revealed the oligoclonal proliferation of infected cells. Although tax gene transcription was suppressed in human PBMC-NOG mice, it increased after in vitro culture. This is similar to the phenotype of HTLV-1-infected cells isolated from HTLV-1 carriers. Furthermore, the reverse transcriptase inhibitors azidothymidine and tenofovir blocked primary infection in human PBMC-NOG mice. However, when tenofovir was administered 1 week after infection, the proviral loads did not differ from those of untreated mice, indicating that after initial infection, clonal proliferation of infected cells was predominant over de novo infection of previously uninfected cells. In this study, we demonstrated that the human PBMC-NOG mouse model should be a useful tool in studying the early stages of primary HTLV-1 infection.

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Section: Discussioncontrasting

confidence: 51%

Section: Significant Increase In the Memory Cd4 ؉ T-cell Population Amentioning

confidence: 99%

De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

Miyazato¹,

Yasunaga²,

Taniguchi³

et al. 2006

J Virol

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“…Some of the cocultivation experiments were performed in the presence of Zerit (Bristol-Myers Squibb Virology, Princeton, NJ) (24). We treated long terminal repeat (LTR)-driven luciferase-expressing Raji cells with or without 35 M of Zerit the day before cocultivation with Jurkat T cells.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Fukumoto

Dundr

Nicot

et al. 2007

J Virol

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The p12I protein of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a small oncoprotein that increases calcium release following protein kinase C activation by phorbol myristate acetate, and importantly, this effect is linker for activation of T cells (LAT) independent. Here, we demonstrate that p12 I inhibits the phosphorylation of LAT, Vav, and phospholipase C-␥1 and decreases NFAT (nuclear factor of activated T cells) activation upon engagement of the T-cell receptor (TCR) with anti-CD3 antibody. Furthermore, we demonstrate that p12 I localizes to membrane lipid rafts and, upon engagement of the TCR, relocalizes to the interface between T cells and antigen-presenting cells, defined as the immunological synapse. A p12 I knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12I curtails viral expression. Thus, p12 I has contrasting effects on TCR signaling: it down-regulates TCR in a LAT-dependent manner on one hand, and on the other, it increases calcium release in a LAT-independent manner. The negative regulation of T-cell activation by p12 I may have evolved to minimize immune recognition of infected CD4 ؉ T cells, to impair the function of infected cytotoxic CD8 ؉ T cells, and to favor viral persistence in the infected host.Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes a rare, aggressive hematopoietic malignancy of mature T cells, designated adult T-cell leukemia/lymphoma, as well as a progressive myelopathy defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (18,20,25,42,55). HTLV-1 infects human CD4 ϩ and CD8 ϩ (22,33,35,39,43) T cells of memory phenotype and is believed to confer a proliferative and survival advantage on infected memory T-cell clones, with consequent accumulation of somatic mutations and neoplastic transformation (16). The provirus is thought to be mostly latent, mainly in resting T cells (21). However, once T cells are stimulated by antigen, the proviral DNA can be expressed, endangering the survival of the infected cells because of immune recognition.The HTLV-1 genome, in addition to structural (Gag and Env) and enzymatic (Pol) proteins, encodes positive regulators of viral expression from open reading frames (ORFs) III and IV, such as Tax and Rex, as well as two negative regulators, p30 II (ORF II) (40) and HBZ, which is encoded from the minus strand RNA (19). ORF I encodes a 12-kDa protein (p12 I ) that in cells is localized in the endoplasmic reticulum (ER)/Golgi (13,28,32). The p12 I protein has been shown to have multiple functions. p12 I interacts with the interleukin-2 receptor (IL-2R) ␤ and ␥ c chains, increases STAT-5 activation, and decreases the threshold of the IL-2 requirement for T-cell proliferation (38, 41) in primary human lymphocytes. In the ER/Golgi, p12 I binds both the IL-2 receptor chains and the major histocompatibility complex (MHC) class I heavy chain and interferes with their trafficking to the cell surface (28, ...

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“…70 For example, in patients with HTLV-1-associated myelopathy (HAM), reduction of HTLV-1 viral DNA load was reported during treatment with the reverse transcriptase inhibitor lamivudine, 71 and HTLV-1 replication was inhibited by the nucleoside reverse-transcriptase inhibitors tenofovir, abacavir, lamivudine, zalcitabine, stavudine, zidovudine and didanosine. 72,73 Another report described the successful treatment of a patient with ATL using zidovudine, lamivudine and IFN-a. 74 Thus, antiretroviral treatment appears to be a promising strategy for the treatment of ATL as a viral infectious disease, but further studies are required in order to elucidate the mechanisms of the anti-ATL effects.…”

Section: New Chemical Anti-tumor Agents 1) Antiretroviral Therapymentioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4 + T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-kB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. 〔J Clin Exp Hematopathol 50(1) : 9-25, 2010〕

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Susceptibility of Human T Cell Leukemia Virus Type I to Nucleoside Reverse Transcriptase Inhibitors

Cited by 47 publications

References 18 publications

De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Treatment of Adult T-cell Leukemia

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Susceptibility of Human T Cell Leukemia Virus Type I to Nucleoside Reverse Transcriptase Inhibitors

Cited by 47 publications

References 18 publications

De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1

Treatment of Adult T-cell Leukemia

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Inhibition of T-Cell Receptor Signal Transduction and Viral Expression by the Linker for Activation of T Cells-Interacting p12 ^I Protein of Human T-Cell Leukemia/Lymphoma Virus Type 1