Epstein–Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

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Adult T-cell leukemia (ATL) is a fatal T-cell malignancy associated with human T-cell leukemia virus type I infection. The aberrant expression of nuclear factor-jB (NF-jB) is considered to contribute to the malignant phenotype and chemo-resistance of ATL cells. Because of the poor prognosis of ATL, the development of new therapeutic strategies is direly needed. In the present study, we show that an IjB kinase 2 (IKK2) inhibitor, IMD-0354, efficiently inhibits the survival of CD4 + CD25+ primary ATL cells and prevents the growth of or induces apoptosis of patient-derived ATL cell lines. Assays of transcription with integrated forms of reporter genes revealed that IMD-0354 suppresses NF-jB-dependent transcriptional activity. Moreover, the daily administration of IMD-0354 prevents the growth of tumors in mice inoculated with ATL cells. Our results suggest that targeting IKK2 with a small molecule inhibitor, such as IMD-0354, is an attractive strategy for the treatment of ATL. (Cancer Sci 2012; 103: 100-106) H uman T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL) and is known to transform T lymphocytes.(1-3) While the majority of infected individuals remain asymptomatic during their lifetime, 2-5% of carriers develop an aggressive form of CD4-positive T-cell leukemia after a long latency period of 50-60 years, and another 0.25-3% of carriers develop a chronic neuro-inflammatory disorder termed HTLV-I-associated myelopathy ⁄ tropical spastic paraparesis.(4-7) At present, there are few established regimens for ATL treatment, mainly because of the intrinsic resistance to conventional drug therapies.(8) Thus, novel therapeutic interventions are urgently required. Although the viral oncoprotein Tax is believed to play a central role in HTLV-I-induced leukemogenesis, (9,10) the expression levels of Tax and other viral proteins are extremely low in leukemic cells freshly isolated from ATL patients and ATL-derived cell lines. (11,12) The tax gene is even mutated or truncated in some ATL cases. (13,14) Thus, Tax might not necessarily be required at later stages of disease progression, and Tax-independent mechanisms are likely to contribute to the proliferation and resistance to apoptosis of leukemic cells. The constitutive activation of nuclear factor-jB (NF-jB) was found in peripheral ATL cells and ATL-derived cell lines, (15) implying important prosurvival roles of NF-jB in ATL cells. Nuclear factor-jB activation has long been implicated in association with multiple processes of oncogenesis, including cell-cycle progression, control of apoptosis, migration, and metastasis.(16) Thus, the inhibition of NF-jB was suggested to be a potential means for cancer therapy in tumors highly expressing NF-jB. (17) We previously reported that a reduction of NF-jB activity by the forced expression of a dominantnegative form of IjBa strongly suppresses the survival of ATL cell lines, and that abrogation of NF-jB activity by a protease inhibitor, ritonavir, significantly prevented the growth ...

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Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs.