Human T-cell lymphotropic virus type I associated adult T-cell leukaemia/lymphoma in Taiwan Chinese

Twenty-five Chinese patients with human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATLL) were identified in Taiwan. No patients had been outside Taiwan and none were descendants of Japanese heritage. Their ages ranged from 28 to 71 years. There were 17 men and eight women. Main clinical and laboratory features at presentation were lymphadenopathy (16), skin lesions (11), hepatosplenomegaly (11), pulmonary lesions (11), hypercalcaemia (10) and bone marrow infiltration (14). Peripheral blood was characterized by leucocytosis with presence of pleomorphic abnormal lymphocytes but rare anaemia or thrombocytopenia. The clinical subtypes were acute in 15, chronic in three, smouldering in one, and lymphoma type in six. The immunophenotypes of the ATLL cells were characterized by the expression of CD2+, CD4+, CD7-, CD8- and CD25+. The overall prognosis was poor with a median survival of 5 months. The acute form had a significantly shorter survival (2 months) than lymphoma type (13 months). Susceptibility to various infections was common. Pulmonary complications accounted for 73% of the causes of death. The clinicopathologic features of ATLL in Taiwan are indistinguishable from those in HTLV-I endemic areas. The present series adds to the knowledge of the worldwide pattern of the disease.     

Human T lymphotropic virus type-I and adult T-cell leukemia in Japan

HTLV-I is the first retrovirus to be associated directly with human malignancy. In ATL-endemic areas, the rate of HTLV-I carriers is high. Both HTLV-I and ATL have been shown to be endemic in some regions of the world, especially in southwest Japan, the Caribbean islands, South Americas, and parts of Central Africa. Antibodies against HTLV-I have been found in over one million individuals, and more than 700 cases of ATL have been diagnosed each year in Japan alone. The cumulative incidence of ATL among HTLV-I carriers in Japan is estimated at 2.5% (3-5% in males, 1-2% in females). In endemic areas, HTLV-I Ab were found in the sera of 6 to 37 percent of healthy adults over 40 years of age. This clustering is thought to be due to the limited transmission of virus between socially isolated populations. The diagnostic criteria for HTLV-I associated ATL have been defined as follows. 1) Histologically and/or cytologically proven lymphoid malignancy with T cell antigens. 2) Abnormal T-lymphocytes present in the peripheral blood, except in the lymphoma type. 3) Serum specimens for all patients with ATL have HTLV-I Ab. 4) Demonstration of clonality of HTLV-I proviral DNA is a definite diagnosis of ATL. ATL shows diverse clinical features but can be divided into four subtypes: acute, chronic, smoldering, and lymphoma type. The pattern of HTLV-I transmission is through one of three different modes. Infected mothers can transmit the virus to newborns mainly via breast milk. The virus also can be transmitted from male to female by sexual intercourse, and through blood transfusion. Chemotherapy is not effective; the acute and lymphoma types have a poor prognosis. ATL is generally treated with curative intent using combination chemotherapy, although long-term success has been very limited. Unfortunately that advance did not translate into an improvement in the overall survival; the median remain 10 months. In contrast, smoldering ATL, or some cases of chronic ATL, may have a more protracted natural course, which may be compromised by aggressive chemotherapy. Alternative strategies for both acute and chronic forms are clearly needed. After infection of HTLV-I, there is a long latent period before onset of ATL. Analyses by PCR showed that clearly proliferation occurred in intermediate state or even carriers with high virus load. Such clonal proliferation might be preleukemic stage, which suggested that carriers with high virus load should be risk group to have ATL.     

Human T-cell lymphotropic virus I and adult T-cell leukemia: report of a cluster in North Carolina

PURPOSE: Human adult T-cell leukemia-lymphoma is a malignant, proliferative disease of CD4+ lymphocytes associated with infection with human T-cell lymphotropic virus type I (HTLV-I). Following the presentation of a patient who was infected with the virus, we undertook a study of his family members and sexual contacts to see if a cluster of infected persons could be identified. CASE REPORT: A black heterosexual North Carolina native with a history of drug abuse presented with jaundice, and pancytopenia subsequently developed. He then became hypercalcemic and leukemic, with high numbers of circulating, morphologically abnormal CD4+ lymphocytes. RESULTS: As determined by radioimmunoassay and immunoblot analyses, the serum of the index case contained antibodies against core proteins (p19 and p24) of HTLV-I. When cultured in vitro with interleukin-2, the lymphocytes expressed HTLV-I specific core proteins. The virus recovered from these T cells was transmitted to cord blood T cells, which became immortalized for continuous growth in vitro, expressed HTLV-I p19 protein, and displayed characteristic C-type particles by electron microscopy. Studies of family members and sexual contacts, all of whom were black, heterosexual central North Carolina natives, revealed five of 28 whose serum had anti-HTLV-I antibodies as determined by radioimmunoassay and immunoblot. Neither the patient nor the seropositive family/contacts had antibodies against human immunodeficiency virus proteins. Four of the six people with HTLV-I infection had no history of intravenous drug abuse. Three of the five seropositive family/contacts had circulating, morphologically abnormal lymphocytes suggestive of "preleukemic" or "smoldering" human adult T-cell leukemia-lymphoma.     

Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells is a characteristic of ATL. Matrix metalloproteinases (MMPs), which mediate the degradation of the basement membrane and extracellular matrix, play an important role in metastasis and tumor cell dissemination. The aim of this study was to explore whether expression of MMP-2 and MMP-9 was deregulated by HTLV-I infection. The data showed that HTLV-I-infected T-cell lines expressed high levels of MMP-9 compared with uninfected T-cell lines. In contrast, the levels of the related MMP-2 were not significantly altered by HTLV-I infection. In addition, the elevated expression of MMP-9 in HTLV-I-infected cells was attributable to the action of the viral transactivator protein Tax. The results show that Tax can activate the MMP-9 promoter and induce MMP-9 expression in T cells, indicating that the constitutive expression of MMP-9 in virus-infected cell lines is at least in part mediated by Tax. Activation of the MMP-9 promoter by Tax occurs mainly through the action of NF-kappaB and SP-1. The biologic significance of these observations was validated by the following 2 findings: MMP-9 expression was increased in primary ATL cells, and plasma MMP-9 levels were elevated in ATL patients. In addition, plasma levels of MMP-9 correlated with organ involvement in ATL patients. Together these data suggest that overexpression of MMP-9 in HTLV-I- infected cells may be in part responsible for the invasiveness of ATL cells.     

Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia-lymphoma in a patient infected with human immunodeficiency virus type 1 (HIV-1)

A patient had adult T-cell leukemia-lymphoma in the unusual setting of coinfection with human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus type I (HTLV-I). The leukemic cells were CD4 positive and showed clonal genetic rearrangement of the T-cell receptor complex. Cytogenetic analysis showed three clonal karyotypic abnormalities: trisomy 3 and two translocations [t(1;15), (X;1)]. The patient was seropositive for HIV and HTLV-I; HTLV-I and HIV-1 DNA sequences were detected in peripheral blood leukocytes by the polymerase chain reaction. The HTLV-I sequences were detected in a relatively high proportion of mononuclear cells (at least 1 in 30 cells), whereas HIV-1 sequences were detected in a smaller proportion of cells (at least 1 in 3000 cells). Clinical remission was achieved after chemotherapy. There was a decrease in the proportion of HTLV-I positive mononuclear cells (at least 1 in 1000 cells), whereas the proportion of HIV-1 positive cells was relatively unchanged (at least 1 in 1000 cells). Adult T-cell leukemia-lymphoma in the setting of HIV coinfection may become increasingly common because asymptomatic retroviral coinfections are frequent.     

Comparison of a human T-cell lymphotropic virus type I strain from cerebrospinal fluid of a Jamaican patient with tropical spastic paraparesis with a prototype human T-cell lymphotropic virus type I.

The isolation and characterization of a human T-cell lymphotropic retrovirus related to human T-cell lymphotropic virus type I (HTLV-I) from cerebrospinal fluid of a Jamaican patient with tropical spastic paraparesis is described. The virus isolate is a typical type C retrovirus as seen by electron microscopy and is related to prototype HTLV-I isolated from patients with adult T-cell leukemia but is not identical to this prototype HTLV-I as seen by restriction enzyme mapping.     

Kaposi's sarcoma in human T-cell leukemia virus type I-associated adult T-cell leukemia

Kaposi's sarcoma (KS) developed in a patient with human T-cell leukemia virus type I (HTLV-I)-associated adult T-cell leukemia who was treated with a short-term course of monoclonal antibody immunotherapy. The presentation was transient and temporally related to the underlying clinical course. The association of KS in an HTLV-I infected, but not human immunodeficiency virus (HIV)-infected, individual should alert investigators to the occurrence of KS in retroviral-associated diseases other than acquired immunodeficiency disease syndrome. Recognition of the similarities and differences between HTLV-I and HIV infections may provide insights concerning the angiopathogenesis of KS.     

Virion-associated trans-regulatory protein of human T-cell leukemia virus type I.

Western blot analysis of HTLV-I virus particles from HUT-102 cells revealed a 40-kD protein strongly reactive with Tax-specific rabbit antisera. This protein subsequently was isolated from density gradient purified virions by preparative sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), purified from comigrating Gag and human cellular proteins by reversed-phase high-performance liquid chromatography (HPLC) and identified as the tax-encoded gene product by amino acid composition analysis. Among extracellular virions from five HTLV-I producing cell lines, only those from HUT-102 and C10MJ cells contained a detectable Tax protein, although all cells expressed Tax mRNA and protein intracellularly. To investigate the diagnostic implications of virion-associated Tax protein, sera from HTLV-I-infected individuals were compared on HUT-102 and MT-2 virus Western blots. The seroprevalence of antibodies to Tax, but not Gag or Env proteins, was substantially higher among adult T-cell leukemia and tropical spastic paraparesis patients using HUT-102 viral proteins. Thus, immunoassays utilizing HUT-102 virus are most sensitive for detection of Tax-reactive antibodies.     

Human monoclonal antibody directed against an envelope glycoprotein of human T-cell leukemia virus type I.

We report the production and characterization of a human monoclonal antibody reactive against the major envelope glycoprotein of human T-cell leukemia virus type I (HTLV-I), a virus linked to the etiology of adult T-cell leukemia. We exposed lymph-node cells derived from a patient with adult T-cell leukemia to the Epstein-Barr virus in vitro and obtained a B-cell clone (designated 0.5 alpha) by a limiting dilution technique. The secreted product of 0.5 alpha is a monoclonal antibody (also designated 0.5 alpha; that is IgG1 and has kappa light chains) that binds to the cell membrane of T-cells infected with HTLV-I and lyses them in the presence of complement. The antibody does not react with HTLV-I-negative T cells. In electroblot assays, the monoclonal antibody detects a 46-kDa glycoprotein in disrupted HTLV-I virions and a 34-kDa product following digestion of the viral protein with endoglycosidase F. These molecules have been reported to represent the HTLV-I env gene products. The antibody does not react with HTLV-II and HTLV-III virions. Glycoproteins of 61 and 68 kDa, which are known to be encoded at least in part by the env gene of HTLV-I, are precipitated by the antibody from endogenously radiolabeled HTLV-I-infected HUT 102-B2 and MT-2 cells, respectively. These results suggest that this human monoclonal antibody reacts with an env-encoded glycoprotein of HTLV-I. By using a competition assay with a biotin-labeled 0.5 alpha antibody, we observed that 15 out of 15 patients with adult T-cell leukemia had antibodies that block binding of the 0.5 alpha antibody to HTLV-I virions. This suggests that the antigen detected by 0.5 alpha antibody is a common epitope recognized in HTLV-I-infected individuals in vivo. This antibody, as well as the general strategy for making human monoclonal antibodies reactive against pathogenic retroviruses, may have diagnostic or therapeutic application.     

Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia

Adult T-cell leukemia (ATL), an aggressive neoplasm of mature helper T cells, is etiologically linked with human T lymphotropic virus type I (HTLV-1). After infection, HTLV-I randomly integrates its provirus into chromosomal DNA. Since ATL is the clonal proliferation of HTLV-I- infected T lymphocytes, molecular methods facilitate the detection of clonal integration of HTLV-I provirus in ATL cells. Using Southern blot analyses and long polymerase chain reaction (PCR) we examined HTLV-I provirus in 72 cases of ATL, of various clinical subtypes. Southern blot analyses revealed that ATL cells in 18 cases had only one long terminal repeat (LTR). Long PCR with LTR primers showed bands shorter than for the complete virus (7.7 kb) or no bands in ATL cells with defective virus. Thus, defective virus was evident in 40 of 72 cases (56%). Two types of defective virus were identified: the first type (type 1) defective virus retained both LTRs and lacked internal sequences, which were mainly the 5' region of provirus, such as gag and pol. Type 1 defective virus was found in 43% of all defective viruses. The second form (type 2) of defective virus had only one LTR, and 5'- LTR was preferentially deleted. This type of defective virus was more frequently detected in cases of acute and lymphoma-type ATL (21/54 cases) than in the chronic type (1/18 cases). The high frequency of this defective virus in the aggressive form of ATL suggests that it may be caused by the genetic instability of HTLV-I provirus, and cells with this defective virus are selected because they escape from immune surveillance systems.     

A novel diagnostic method of adult T-cell leukemia: monoclonal integration of human T-cell lymphotropic virus type I provirus DNA detected by inverse polymerase chain reaction

Adult T-cell leukemia (ATL) is neoplasm of the mature helper T lymphocytes and human T-cell lymphotropic virus type-I (HTLV-I) has been shown to be causative virus of ATL. Because HTLV-I integrates its provirus randomly into host chromosomal DNA, monoclonal integration of HTLV-I provirus indicates the clonal proliferation of HTLV-I-infected cells. Therefore, demonstration of clonality of HTLV-I proviral DNA is essential to diagnosis of ATL. Southern blot analysis was used for this purpose. We developed the novel method using inverse polymerase chain reaction (IPCR) to detect the clonality of HTLV-I proviral DNA. This method identified the clonality in all ATL cases. Diagnosis could be made within 3 days using this method. It enabled us to detect specifically the presence of minimal numbers of ATL cells with high sensitivity. It also identified the monoclonal or oligoclonal proliferations of HTLV-I-infected cells in HTLV-I carriers and the intermediate state, in which no clonality could be shown by conventional Southern blot analyses. This finding indicated that even HTLV-I carriers had monoclonal proliferation of HTLV-I-infected cells without any symptoms. This novel method is shown to be useful for the diagnosis of ATL and provides information on the natural course of HTLV- I infection.