Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I)

Infection with human T-cell lymphotrophic virus-I (HTLV-I) is now a global epidemic, affecting 10 million to 20 million people. This virus has been linked to life-threatening, incurable diseases: adult T-cell leukemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The cumulative lifetime risk of developing these incurable diseases is approximately 5% in asymptomatic patients. For the emergency physician practicing among patients from high-risk groups, HTLV-I and its associated diseases are presenting an increasing challenge. This report describes its transmission, seroprevalence, treatment, and methods of controlling spread of this retrovirus. Coinfection with HTLV-I and HIV has been shown to accelerate the progression of acquired immune deficiency syndrome (AIDS).     

Human T-cell lymphotrophic virus type-I (HTLV-I) retrovirus and human disease

Human T-cell lymphotrophic virus type-I (HTLV-I) was the first pathogenic retrovirus identified in humans. HTLV-I is now linked to a number of clinical diseases, most notably adult T-cell leukemia/lymphoma and the syndrome known as HTLV-associated myelopathy or tropical spastic paraparesis (HAM/TSP). For the emergency physician practicing among patients from high-risk groups, HTLV-I infection and its associated diseases are presenting an increasing challenge. This report describes its transmission, seroprevalence, associated diseases, and methods to control the spread of this retrovirus.     

Monoclonal antibody against human T cell leukemia virus p19 defines a human thymic epithelial antigen acquired during ontogeny

Using monoclonal antibody 12/1-2 against a 19,000-dalton human T cell leukemia virus (HTLV) protein (anti-p19), previously demonstrated to be reactive with HTLV-infected human cells, but not in numerous other uninfected cells, we found a reactive antigen to be expressed on the neuroendocrine component of human thymic epithelial cells but not on any other normal epithelial or neuroendocrine human tissues. Moreover, this reactive antigen is acquired on neuroendocrine thymic epithelium during thymic ontogeny--first appearing on fetal thymic epithelial cells between 8 and 15 wk gestation. While only a portion of thymic epithelial cells in the subcapsular cortical region of 15- and 24-wk fetal thymuses contained anti-p19+ epithelial cells, the entire subcapsular cortical region of newborn thymus epithelium was anti-p19+. By age 3 yr, normal subjects' entire subcapsular cortical and medullary thymic epithelium was anti-p19+. Using antibody against HTLV core protein, p24, and c-DNA probes for HTLV DNA, neither HTLV-specific p24 protein nor proviral DNA could be demonstrated in anti-p19+ thymic epithelial tissue. However, thymic epithelial extracts, disrupted HTLV extracts, as well as purified HTLV p19 antigen all inhibited the binding of anti-p19 antibody to thymic epithelium. Thus, anti-p19 may recognize a determinant on an HTLV-encoded 19,000-dalton structural protein that is shared by human thymic epithelium. Alternatively, anti- p19 defines a host encoded protein that is selectively expressed by normal thymic epithelium, and is induced to be expressed in HTLV- infected malignant T cells.     

Induction of pro-inflammatory cytokines by human T-cell leukemia virus type-1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by a hyperstimulated immune response, including elevated levels of inflammatory cytokines/chemokines and oligoclonal expansion of virus-specific CD8(+) T cells in the cerebrospinal fluid. Studies have shown that the HTLV-1 transactivator protein Tax is available for immune recognition by antigen presenting cells (APCs), such as dendritic cells (DCs). DCs are relevant to the pathogenesis of HAM/TSP because the presentation of Tax peptides by activated DCs to na?ve CD8(+) T cells may play an important role in the induction of the Tax-specific immune response that is observed in HAM/TSP. In this study, a human cytokine protein array was used to study the secretion of cytokines by monocyte-derived DCs (MDDCs) exposed to Tax. Of the 16 cytokines analyzed, 6 cytokines were secreted in significantly high amounts (> or =2-fold), including Th1 cytokines (IFN-gamma, IL-12, and TNF-alpha) and C-C chemokines (Eotaxin, MCP-1, and MCP-3). Selected cytokines were further examined at two concentrations of Tax and at two time periods. Furthermore, a transient exposure to Tax did not result in any cytokine production when examined at three different time points after exposure, indicating that a prolonged presence of Tax is required for its activity. Finally, inhibition of the NF-kappaB signaling pathway by specific inhibitors, abrogated Tax-mediated cytokine secretion. Collectively, these findings suggest a role for Tax-induced cytokine secretion from MDDCs, which may be critical for the cellular activation and tissue damage that has been observed in HAM/TSP.     

NIK-333 inhibits growth of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells in association with blockade of nuclear factor-kappaB signal pathway

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. NIK-333, a novel synthetic retinoid, prevents the recurrence of human hepatoma after surgical resection of primary tumors. We explored the effects of NIK-333 on HTLV-I-infected T-cell lines and ATL cells. NIK-333 inhibited cell proliferation, induced G1 arrest, and resulted in massive apoptosis in all tested HTLV-I-infected T-cell lines and ATL cells, whereas little effect was observed on normal peripheral blood mononuclear cells. NIK-333 treatment decreases the levels of cyclin D1, cyclin D2, cIAP2, and XIAP proteins. Further analysis showed that NIK-333 inactivated nuclear factor-kappaB in HTLV-I-infected T-cell lines. In animal studies, treatment with NIK-333 (100 mg/kg given orally every other day) produced partial inhibition of growth of tumors of a HTLV-I-infected T-cell line transplanted s.c. in severe combined immunodeficient mice. Our results indicate that NIK-333 is a potentially useful therapeutic agent for patients with ATL.     

Monoclonal antibodies directed against the rev protein of human immunodeficiency virus type 1

The rev (art/trs) protein of human immunodeficiency virus type 1 (HIV-1), a phosphoprotein of 20 K apparent molecular weight, is essential to target the mRNA for virion polypeptides into the cytoplasm. The rev protein was expressed in Escherichia coli as a beta-galactosidase fusion protein with a cleavage site for proteinase factor Xa. The rev-specific fragment was isolated to immunize mice. Five stable hybridoma cell lines were obtained producing monoclonal antibodies that reacted with rev protein in Western blot and ELISA. Using the monoclonal antibodies in indirect immunofluorescence, the rev protein could be localized in the nucleus, mostly in the nucleoli, of Hela cells that were transfected with a eukaryotic rev expression plasmid.     

佛山市无偿献血者人类T淋巴细胞白血病病毒感染情况调查

目的 探讨广东省佛山市无偿献血人群中,人类T淋巴细胞白血病病毒(HTLV)感染状况,评估经血液传播HTLV的风险,保障临床输血安全.方法 选择2016年2月至12月,于佛山市参加无偿献血的69 275例献血者作为研究对象.采用酶联免疫吸附试验(ELISA)法对献血者血浆中HTLV-Ⅰ/-Ⅱ抗体进行初步筛查.对初检结果呈反应性的标本再进行双孔复检.对复检结果呈反应性的标本,则判定为HTLV-Ⅰ/-Ⅱ抗体初筛结果呈阳性.对初筛结果呈阳性的标本采用Western印迹法进行确证.统计不同性别、年龄、学历、户籍及献血次数献血人群的HTLV-Ⅰ/-Ⅱ抗体的初筛阳性率,并且采用统计学方法,分别对不同献血人群的HTLV-Ⅰ/-Ⅱ抗体初筛阳性率进行比较.结果 ①本研究69 275例无偿献血者中,HTLV-Ⅰ/-Ⅱ抗体呈阳性者为17例,HTLV-Ⅰ/-Ⅱ抗体初筛阳性率为0.025％.其中,仅2例献血者的HTLV-Ⅰ/-Ⅱ抗体的Western印迹法确证试验结果呈阳性,确证阳性率为0.003％.②本研究69 275例无偿献血者中,女性献血者的HTLV-Ⅰ/-Ⅱ抗体初筛阳性率为0.042％(11/26 291),高于男性的0.014％(6/42 984),并且差异有统计学意义(x2=5.17,P=0.023).不同年龄段献血者中,46～55岁年龄段献血者的HTLV-Ⅰ/-Ⅱ抗体初筛阳性率最高(0.084％,4/4 768);并且不同年龄段献血者HTLV-Ⅰ/-Ⅱ抗体初筛阳性率总体比较,差异有统计学意义(x2=8.09,P=0.044).不同学历献血者中,初中及以下学历献血者HTLV-Ⅰ/-Ⅱ抗体初筛初筛阳性率最高(0.063％,7/11 113);并且不同学历献血人群HTLV-Ⅰ/-Ⅱ抗体初筛阳性率总体比较,差异有统计学意义(x2 =7.97,P=0.047).外地户籍献血者HTLV-Ⅰ/-Ⅱ抗体初筛阳性率(0.033％,15/45 274)高于本地户籍献血者(0.008％,2/24 001),并且差异有统计学意义(x2=3.93,P=0.047).2次及以上献血者HTLV-Ⅰ/-Ⅱ抗体初筛阳性率(0.034％,16/46 414)高于首次献血者(0.004％,1/22 861),并且差异有统计学意义(x2=5.65,P=0.017).结论 佛山市属于无偿献血人群感染HTLV的低发生率区或者非流行区.女性、老年、学历低、外地户籍及多次献血的无偿献血人群感染HTLV的风险较大.鉴于输血安全,建议献血前常规检测所有无偿献血者的HTLV-Ⅰ/-Ⅱ抗体,同时对血液进行去除白细胞过滤处理.     

Monoclonal antibody defining a molecule possibly identical to the p75 subunit of interleukin 2 receptor

A mouse hybridoma cell line, TU27, producing an mAb was established. TU27 mAb reacted with various human and Gibbon ape T cell lines bearing the IL-2R p75 (IL-2Rp75), but not with cell lines expressing only Tac antigen, IL-2Rp55, and numbers of its binding sites on cell surfaces were similar to those of high-affinity IL-2R. Radioimmunoprecipitation with TU27 mAb defined a molecule with a molecular mass of 75 kD on the surface of IL-2Rp75 bearing cells. TU27 mAb completely blocked IL-2 binding to IL-2Rp75 and to the high-affinity IL-2R but not to IL-2Rp55 composing the low-affinity IL-2R. The IL-2-dependent growth of a human T cell line, ILT-Mat, was significantly inhibited by TU27 mAb only at low concentrations of IL-2, and combination of TU27 mAb and H-31 mAb specific for IL-2Rp55 completely inhibited the cell growth even at high concentrations of IL-2. These data strongly suggest that TU27 mAb is specific for the human IL-2Rp75.     

Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor.

Adult T cell leukemia (ATL) and Sézary leukemia are malignant proliferations of T lymphocytes that share similar cell morphology and clinical features. ATL is associated with HTLV (human T cell leukemia/lymphoma virus), a unique human type C retrovirus, whereas most patients with the Sézary syndrome do not have antibodies to this virus. Leukemic cells of both groups were of the T3, T4-positive, T8-negative phenotype. Despite the similar phenotype, HTLV-negative Sézary leukemic cells frequently functioned as helper cells, whereas some HTLV-positive ATL and HTLV-positive Sézary cells appeared to function as suppressors of immunoglobulin synthesis. One can distinguish the HTLV-positive from the HTLV-negative leukemias using a monoclonal antibody (anti-Tac) that appears to identify the human receptor for T cell growth factor (TCGF). Resting normal T cells and most HTLV-negative Sézary cells were Tac-negative, whereas all ATL cell populations were Tac-positive. The observation that ATL cells manifest TCGF receptors suggests the possibility that an abnormality of the TCGF-TCGF receptor system may partially explain the uncontrolled growth of these cells.     

北京地区部分献血员嗜人T细胞病毒I型血清抗体调查

目的 进一步了解北京地区献血员HTLV-I感染状况。方法 应用明胶颗粒凝集试验(GPAT)检测本院的749份北京地区献血员血清HTLV-I抗体。结果 均为阴性。结论 研究结果可能与近年来北京地区对献血员的严格筛选有关,其它病毒检测项目的增加可能也会减少血清HTLV-I的阳性率。     

Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells.

HTLV-1 infection causes an adult T cell leukemia in humans. The viral encoded protein tax, is thought to play an important role in oncogenesis. Our previous data obtained from a tax transgenic mouse model revealed that tax transforms mouse fibroblasts but not thymocytes, despite comparable levels of tax expression in both tissues. Constitutive tyrosine phosphorylation of a 130-kD protein(s) was observed in the tax transformed fibroblast B line and in HTLV-1 transformed human lymphoid lines, but not in thymocytes from Thy-tax transgenic mice. Phosphotyrosine immunoprecipitation followed by Western blot analysis with a set of Jak kinase specific antibodies, identified p130 as Jak2 in the tax transformed mouse fibroblastic cell line and Jak3 in HTLV-1 transformed human T cell lines. Phosphorylation of Jak2 in tax transformed cells resulted from high expression of IL-6. Tyrosine phosphorylation of this protein could also be induced in Balb/c3T3 cells using a supernatant from the B line, which was associated with induction of cell proliferation. Both phosphorylation and proliferation were inhibited by IL-6 neutralizing antibodies. Constitutive phosphorylation of Jak kinases may facilitate tumor growth in both HTLV-1 infected human T cells and the transgenic mouse model.