Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tropical spastic paraparesis/human T-cell leukemia-lymphoma virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic neurological illness epidemiologically associated with HTLV-I infection. We investigated the role of HTLV-I in the pathogenesis of this disease by studying viral expression in fresh uncultured peripheral blood mononuclear cells (PBMCs) of six patients of Caribbean origin with TSP/HAM. The PBMC genomic DNA of all the patients studied carried HTLV-I provirus, but viral expression was not detected by Northern (RNA) blot analysis of total cellular PBMC RNA. When the reverse transcriptase polymerase chain reaction technique was used with primers specific for the tax-rex mRNA, all of the samples were positive for this viral mRNA species, regardless of the duration of the illness (range, 2 to 13 years). The splice junctions for the tax-rex mRNA described in cases of HTLV-I-induced adult T-cell leukemia (position 5183 of the envelope and position 7302 of the pX region) were identical in three TSP/HAM cases studied. To ascertain whether viral expression occurred at a low level in many cells or at a high level in a few permissive cells, we performed in situ hybridization on fresh PBMCs from two patients (2 and 7 years after clinical diagnosis), seeking HTLV-I RNA sequences. Our finding indicated that in vivo HTLV-I expression occurred at a high level in a few cells (1 of every 5,000 PBMCs) in both cases studied. The fact that cells of all six patients with TSP/HAM were positive for viral expression, regardless of the time lag from diagnosis, suggests that persistent expression of a viral product(s) may be pivotal in the pathogenesis of TSP/HAM.
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PMID:Human T-cell leukemia-lymphoma virus type I (HTLV-I) expression in fresh peripheral blood mononuclear cells from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy. 199 55

Seventeen patients with adult T-cell leukemia (ATL) and 21 with tropical spastic paraparesis/human T-cell leukemia/lymphoma virus type I (HTLV-I)-associated myelopathy (TSP/HAM) were observed during a 3-yr survey (1986-1988) in some hospitals in Paris, France. Most of them were black, originating from high-HTLV-I-endemic areas (West Indies or Africa), but two cases of TSP/HAM occurred in French Caucasians. In one case, the patient acquired the virus from a transfusion during a cardiac transplantation. Most of the ATL cases were diagnosed as acute leukemia or lymphoma, with a proliferation of CD2+, CD3+, CD4+, CD8-, DR+, and CD25+ lymphoid cells. Only three cases were diagnosed as a smoldering ATL. All of the TSP/HAM cases exhibited a spastic paraparesis with a chronic and slow evolution and high HTLV-I antibody titers in serum and cerebrospinal fluid, with a high HTLV-I antibody index and specific HTLV-I immunoglobulin = oligoclonal bands. In TSP/HAM, a high percentage of DR-expressing cells (15 to 40%) was found, with a slightly elevated CD4/CD8 ratio. This was associated with the presence of 1 to 10% abnormally shaped nuclei in lymphoid cells and a polyclonal integration of HTLV-I proviruses in these peripheral blood mononuclear cells. On the contrary, a clonal integration was always found in the ATL malignant cells (leukemic, lymph node, and cutaneous infiltrate). Long-term interleukin 2-dependent T-cell lines (CD2+, CD3+, CD4+, and WT31+) with activated T-cell markers (CD25+ and DR+) producing HTLV-I were established from ATL and TSP/HAM peripheral blood mononuclear cells.
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PMID:Epidemiology and immunovirology of human T-cell leukemia/lymphoma virus type I-associated adult T-cell leukemia and chronic myelopathies as seen in France. 220 41

A state of T-cell activation, reflected by a marked degree of spontaneous proliferation in vitro, exists among patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) but not in those with retroviral-induced adult T-cell leukemia (ATL). We wished to define the mechanism by which the immune activation of circulating cells from HAM/TSP is driven, thus gaining insight into the pathogenesis of this HTLV-I-associated disease. By using a modification of the polymerase chain reaction, we compared the levels of interleukin 2 (IL-2) and IL-2 receptor alpha chain (IL-2R alpha) mRNA expression to the transcription of the HTLV-I transactivator gene, pX, in peripheral blood mononuclear cells of HAM/TSP and ATL patients as well as seropositive carriers. Up-regulation of IL-2 and IL-2R alpha transcripts was detected in HAM/TSP and seropositive carriers that paralleled the coordinate mRNA expression of the pX transactivator. In addition, IL-2 and soluble IL-2R alpha serum levels in HAM/TSP and seropositive carriers were elevated. Despite markedly elevated levels of soluble IL-2R alpha in ATL, transcripts for IL-2 and pX were not demonstrable in the circulating cells. Finally, the marked degree of in vitro spontaneous proliferation present in HAM/TSP was profoundly inhibited by specific anti-IL-2R or anti-IL-2 blocking antibodies. Collectively, these results suggest that immune activation in HAM/TSP, in contrast to ATL, is virally driven by the transactivation and coordinate expression of IL-2 and IL-2R alpha. This deregulated autocrine process may contribute to the evolution of inflammatory nervous system damage in HAM/TSP.
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PMID:Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. 236 34

Eventually, gene therapy may be a valid option for chronic viral infections, including retroviral infections. Human retroviral diseases fit two categories: (1) those that result from a monoclonal outgrowth of a human T-cell leukemia virus type I (HTLV-I)-infected cell, as in the case of adult T cell leukemia (ATL); and (2) those that appear to result directly from virus load rather than monoclonal outgrowth--such as tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM) and human immunodeficiency virus (HIV)-associated acquired immune deficiency syndrome (AIDS). For ATL gene therapy, corrective mechanisms directed at regulatory sequences rather than viral sequences may be most important, though perhaps anti-tax therapy would be useful. For TSP/HAM and AIDS, gene therapy directed to control virus replication may be most useful. For anti-retroviral therapy, one may use dominant negative mutants and a variety of other approaches that direct toxins or compete out viral regulatory gene signal sequences. For maximum benefit, such therapy should be directed to different essential genes (eg gag, pol, env, tat or rev) involved in the virus replication cycle and utilize different toxic approaches. A major impediment to the use of gene therapy for AIDS is our inability to transfect a significant fraction of target cells in vivo. Except for reconstituted mice, retroviral systems of animals have been under-utilized as models for gene therapy. Naturally occurring retroviral diseases of cats, goats, horses, and other species provide models for future development.
Leukemia 1995 Oct
PMID:Gene therapy against retroviral diseases. 747 20

Adult T cell leukemia (ATL) is the T cell malignancy caused by human T lymphotropic virus type I (HTLV-I), and HTLV-I is also the causative agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although HTLV-I causes both diseases, concomitant occurrence is reported to be rare. This paper describes two cases of HAM/TSP that developed into lymphoma-type ATL after the onset of HAM/TSP. In one case, the same HTLV-I infected clone could be detected by polymerase chain reaction in peripheral blood obtained when the patient was diagnosed as HAM/TSP. This finding showed that the HTLV-I clone already existed at the stage of HAM/TSP. Since frequent detection of clonal proliferation of HTLV-I infected cells has been reported previously in patients with HAM/TSP, careful follow-up is needed for patients with HAM/TSP.
Leukemia 1995 Oct
PMID:Adult T cell leukemia following HTLV-I-associated myelopathy/tropical spastic paraparesis: case reports and implication to the natural course of ATL. 756 23

Some Brazilian regions are considered to be endemic for human T-cell leukemia/lymphoma virus type I (HTLV-I) infection. Several studies have shown a high prevalence of HTLV-I infection among different groups such as blood donors, hemophiliacs and patients suffering from hematological and neurological diseases. Cases of adult T-cell leukemia/lymphoma as well as tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) have already been described in Brazil. We report the isolation of an HTLV-I strain from cultured lymphocytes of a TSP/HAM patient. An IL-2-dependent HTLV-I-infected T-cell line (ROB) expressing viral antigens was established and reverse transcriptase activity could be detected in the culture supernatant. Ultrastructural analysis showed immature and mature HTLV retrovirus particles. Finally, HTLV-I provirus type I was demonstrated by the polymerase chain reaction. This is the first isolation completely carried out in Latin America. The molecular analysis of viral strains, now in progress, should clarify the molecular epidemiology of HTLV-I in Brazil.
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PMID:Detection and isolation of human T-cell leukemia/lymphoma virus type I (HTLV-I) from cultured lymphocytes of a Brazilian TSP/HAM patient. 758 Oct 28

Human T-cell leukemia virus type I (HTLV-I) is associated with a large spectrum of clinical manifestation including adult T-cell leukemia (ATL) and tropical spastic paraparesis or HTLV-I-associated myelopathy (TSP/HAM). In most cases, however, infected patients remain asymptomatic. The participation of the immune system in the pathogenesis of TSP/HAM has been suggested. In this study the IgG antibody response of HTLV-I-infected individuals has been investigated using both ELISA with a panel of nuclear and cytoplasmic proteins and peptides known to be recognized by antibodies from patients with various systemic autoimmune diseases, and immunoprecipitation of ribonucleoproteins from HeLa cell extracts. The results were compared with the reactivity of sera from individuals with non-HTLV-I-related neurological diseases and healthy blood donors. Raised levels of autoantibodies reacting with several nuclear and cytoplasmic antigens were found in TSP/HAM and ATL patients. In asymptomatic HTLV-I-seropositive individuals, both the prevalence and level of IgG antibodies were lower and directed only against a restricted set of antigens. The mechanism of induction of these antibodies still remains obscure. However, the results show that a significant autoimmune response exists in these patients and it may contribute to the pathogenesis of the disease.
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PMID:IgG autoantibody response in HTLV-I-infected patients. 758 38

Human T-cell-leukemia virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). The different disease outcome may be attributable to subtle mutations leading to modification of viral tropism or infectivity. Initial attempts found a very high level of sequence conservation among all HTLV-I strains. However, only one complete proviral DNA sequence is reported from a TSP/HAM patient, with a provirus derived from immortalized lymphocytes, which might be expected to be a leukemogenic variant rather than a neurotropic one. We cloned and sequenced a complete HTLV-I provirus (HTLV-IBoi) derived from the uncultured lymphocytes of a sub-acute post-transfusional TSP/HAM patient with clonal integration of HTLV-I. HTLV-IBoi proviral genome is 9033 bp long, and its overall genetic organization is similar to that of the prototype HTLV-I(ATK), without major deletions or insertions. No premature termination codon was found in the 4 open reading frames of the pX region. Divergence at the nucleotide level of HTLV-IBoi from the reported full-length HTLV-I varies from 1 to 9.4%, and indicates that it corresponds to a cosmopolitan genotype. This study did not identify specific sequences associated with neurotropic strains.
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PMID:Human T-cell-leukemia virus type I in post-transfusional spastic paraparesis: complete proviral sequence from uncultured blood cells. 759 Dec 56

We searched for the presence of human T-cell leukemia virus type I (HTLV-I) sequences in central nervous system and muscle lesions of 3 patients with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and 3 patients with HTLV-I-associated polymyositis. Proviral DNA coding for the Tax protein was found by polymerase chain reaction amplification in DNA extracted from lesions of every patient with TSP/HAM or HTLV-I-associated polymyositis. In contrast, viral RNA was found occasionally by in situ hybridization in muscle lesions of some patients with polymyositis, but was never found in central nervous system lesions of TSP/HAM patients.
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PMID:A search for human T-cell leukemia virus type I in the lesions of patients with tropical spastic paraparesis and polymyositis. 766 33

Patients with human T-cell leukemia virus type-1 (HTLV-1)-associated myelopathy (HAM/TSP) generally harbor a much greater population of HTLV-1-infected T cells in peripheral blood mononuclear cells (PBMCs) than asymptomatic carriers. These cells are not malignant but frequently proliferate clonally. To investigate the possibility that higher expression of the viral activator Tax induces preferential proliferation of infected nonmalignant T cells in HAM/TSP patients, the expression of Tax mRNA in fresh PBMCs was analyzed by reverse transcriptase-mediated polymerase chain reaction. Total amount of Tax mRNA was higher in HAM/TSP patients than in carriers, but the expression level was almost the same as that in asymptomatic carriers when compared per infected cell. The expression levels in adult T-cell leukemia patients were significantly lower than those in HAM/TSP patients and asymptomatic carriers. These results indicate that tax gene is not expressed at a continuously high level in HAM/TSP patients who carry a high population of infected T cells, even in those with clonally proliferated infected T cells.
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PMID:Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells. 770 92


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