Human T-cell Lymphotrophic virus-I Research Articles

An Update on the Global Epidemic of Human T-Cell Lymphotrophic Virus Type-I (HTLV-I)

Infection with human T-cell lymphotrophic virus-I (HTLV-I) is now a global epidemic, affecting 10 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), as well as several chronic illnesses, such as uveitis and dermatitis. The cumulative lifetime risk of developing these incurable diseases is approximately 5% in asymptomatic patients. For operating room personnel performing surgery 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 public health initiatives that must be instituted to prevent the spread of this retrovirus. Coinfection with HTLV-I and human immunodeficiency virus (HIV) has been shown to accelerate the progression of acquired immune deficiency syndrome (AIDS).

Hand osteolysis in patients with adult T-cell leukemia-lymphoma: radiographic characteristics.

Adult T-cell leukemia-lymphoma (ATLL) is caused by human T-cell lymphotrophic virus I (HTLV-I) infection. Among ATLL cases, 70% of patients present with leukemia and the remaining patients present with lymphoma. Hand osteolysis in the patients with ATLL is considered as paraneoplastic syndrome and caused by parathyroid hormone-related peptide (PTHrP) released from tumor cells. Radiographic features are similar to hyperparathyroidism, but the distribution of osteolysis in hands appears to be slightly different with the authors' experiences. The objective of this study was to identify radiographic characteristics of hand osteolysis associated with ATLL. We included six ATLL patients (5 men and 1 woman; age range, 45-71 years). All the patients presented with acute leukemia, and three were associated with hypercalcemia and pain in various locations including hands. Patterns of osteolysis on hand radiographs were evaluated and recorded independently by three musculoskeletal radiologists. We analyzed the distribution of the bone resorption in the ray distribution of the hand, finger predilection, and the difference between the ulnar and radial sides. The bone resorption was characterized by frequent involvement of the distal and proximal phalanges, predilection of ring fingers and prominent involvement on the ulnar side, compared with frequent involvement of proximal and middle phalanges, index and middle fingers, and on the radial side in the bone resorption of typical hyperparathyroidism. Such distribution may be a characteristic feature of hand osteolysis in patients with ATLL. The present findings are helpful for physicians to differentiate PTHrP-mediated osteolysis in ATLL from parathyroid hormone-mediated hyperparathyroidism.

Evidence of multiple infectious agents in mycosis fungoides lesions

The etiology of mycosis fungoides (MF) remains to be determined. Several studies have proposed a viral etiology with controversial results. In this case–control study we investigated the presence of Epstein–Barr virus (EBV) and the debated presence of Human T-cell lymphotrophic virus I (HTLV-I) sequences, by polymerase chain reaction on nucleic acid extracts from formalin-fixed paraffin-embedded skin biopsies. Moreover, by a multivariate approach we analyzed in the same case–control study also the contribution of two previously examined pathogens: Hepatitis C virus (HCV) and Borrelia burgdorferi (Bb). Significant differences in the frequency of infectious agents in cases and controls were detected for Bb, HTLV-I and EBV. In MF patients we found the concurrent presence of two or three of these pathogen sequences in 21 out of 83 cases, but only in 1 out of 83 healthy controls. Our results suggest that the persistence of multiple infectious agents may cause a long-term antigenic stimulation contributing to the malignant transformation of T lymphocytes, especially when associated with HTLV-I like sequences. However, these infectious agents do not seem to have effects on disease progression.

Localization of ligand-binding sites on human C1q globular head region using recombinant globular head fragments and single-chain antibodies

As a charge pattern recognition molecule, human C1q can bind a range of immunoglobulin and non-immunoglobulin ligands via its carboxy-terminal globular domain and activate the classical complement pathway. Each globular domain has a heterotrimeric organization, composed of the carboxy-terminal halves of one A (ghA), one B (ghB), and one C (ghC) chain . Recently, we have found that the recombinant forms of individual ghA, ghB and ghC bind differentially to IgG, IgM, gp41 peptide 601–613 of human immunodeficiency virus-1 (HIV-1), gp21 peptide 400–429 of human T cell lymphotrophic virus-I (HTLV-I), β-amyloid peptide, and apoptotic cells, suggesting a modular organization of the globular domain. This paper examines the interaction of ghA, ghB and ghC with two known C1q ligands: Klebsiella pneumoniae porin OmpK36 and salivary agglutinin. In addition, we have used a panel of recombinant single-chain antibodies (scFv) specific for ghA, ghB and ghC in order to map sites on the heterotrimeric globular domain which are likely to interact with IgG1, IgG3, IgM, OmpK36, salivary agglutinin and gp41 loop peptide. The combined use of recombinant ghA, ghB, ghC and single-chain antibodies has revealed at least three ligand-binding sites on the globular domain of C1q: one is IgG- and OmpK36-specific, the second (IgM-binding site) is most likely overlapping with IgG/OmpK36 binding site, and the third (the gp41-binding site) seems to be located at the junction between the collagen and globular domains.

Global epidemic of human T-cell lymphotrophic virus type-I (HTLV-I): an update.

Infection with human T-cell lymphotrophic virus-I (HTLV-I) is now a global epidemic, affecting 10 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), as well as several chronic illnesses, such as uveitis and dermatitis. The cumulative lifetime risk of developing these incurable diseases is approximately 5% in asymptomatic patients. For operating room personnel performing surgery 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 public health initiatives that must be instituted to prevent the spread of this retrovirus. Coinfection with HTLV-I and human immunodeficiency virus (HIV) has been shown to accelerate the progression of acquired immune deficiency syndrome (AIDS).

Spectrum of myelopathies in HIV seropositive South African patients.

The authors determined the cause of myelopathies in 33 HIV seropositive individuals in KwaZulu/Natal, South Africa. The main associations were with human T-cell lymphotrophic virus-I, tuberculosis, herpes zoster, and syphilis. A novel association with probable bilharziasis was noted. Only one case of vacuolar myelopathy was identified. Opportunistic infections will probably persist until routine antiretroviral therapy becomes widely available in South Africa.

Examination of CD8+ T Cell Function in Humans Using MHC Class I Tetramers: Similar Cytotoxicity but Variable Proliferation and Cytokine Production Among Different Clonal CD8+ T Cells Specific to a Single Viral Epitope

Following infection by human T cell lymphotrophic virus-I (HTLV-I), high frequencies of polyclonal Tax11-19-reactive CD8(+) T cells can be detected in the peripheral blood. To investigate whether there are differences in the effector functions of these cells, we generated a panel of Tax11-19-reactive T cell clones by single cell sorting of HLA-A2/Tax11-19 tetramer binding CD8(+) T cells followed by repeated stimulation with PHA and IL-2. Examination of the TCRs revealed 17 different T cell clones with unique clonal origins. Nine representative CD8(+) T cell clones showed a similar cytotoxic dose-response activity against Ag-pulsed target cells, even though they express different TCRs. This cytotoxic effector function was not influenced by the engagement of either CD28 or CD2 costimulatory molecules. In contrast to the cytotoxic activity, qualitatively different degrees of proliferative response and cytokine secretion were observed among T cell clones of different clonal origin. The induction of proliferation and cytokine secretion required the engagement of costimulatory molecules, particularly CD2-LFA-3 interaction. These results indicate that functionally diverse, polyclonal CTL populations can be activated specific to a single immunodominant viral epitope; they can manifest virtually identical cytotoxic effector function but have marked differences in proliferation and cytokine secretion.

Serum S100B levels in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis

Human T-cell lymphotrophic virus–I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive neurologic illness caused by HTLV-I. HAM/TSP is endemic in Brazil1 and, although there are some interregional differences in neurologic manifestations, the main clinical findings are similar to those previously described.1,2 The lifetime risk among HTLV-I carriers to develop HAM/TSP is less than 2%.2 As in several other chronic inflammatory or neurodegenerative diseases, it would be helpful to identify sensitive or specific clinical or complementary tests to detect early pathologic lesions, to follow up disease progression, or to predict which asymptomatic HTLV-I–positive patients will develop HAM/TSP. Recently, a quantitative assessment of muscle spasticity showed subclinical increased lower extremity tone in female commercial sex workers positive for HTLV-I.3 The relevance of this finding to HAM/TSP development remains unknown.3 Viral mRNA of HTLV-I was found in astrocytes of patients with HAM/TSP …

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).

Development and validation of a Western immunoblot assay for detection of antibodies to porcine endogenous retrovirus.

Reports that pig endogenous retrovirus (PERV) infects human cells in vitro have heightened the importance of molecular and serologic monitoring of xenograft recipients for evidence of infection with PERV. We report the development and validation of a PERV-specific Western immunoblot assay for the diagnostic testing of porcine xenografts recipients. This assay is based upon the serological cross-reactivity observed between PERV variants capable of infecting human cells in vitro and other mammalian C type retroviruses. Strong reactivity between PERV expressing embryonic pig kidney PK-15 cells and antisera raised against whole virus preparations of murine leukemia virus, gibbon ape leukemia virus (GALV), and simian sarcoma-associated virus was demonstrated by an immunofluorescence assay, suggesting specific antigenic cross-reactivity between this group of viruses and PERV. Western immunoblot analysis demonstrated that anti-GALV antisera reacted with three proteins in PK-15 cells having molecular masses of 30, 55, and 66 kDa. Antisera specific for the Gag proteins of either GALV or simian sarcoma-associated virus reacted with the 30-kDa (major) and 55-kDa (minor) proteins present in PK-15 cells and in PERV-infected 293 human kidney cells, likely representing reactivity to the processed and precursor forms of the PERV Gag protein, respectively. No reactivity was seen in uninfected 293 cells. Analysis of plasma samples from 200 United States blood donors and from 58 human immunodeficiency virus-1, 18 human immunodeficiency virus-2, 13 human T-cell lymphotrophic virus-I, 21 human T-cell lymphotrophic virus-II, and 15 cytomegalovirus infected controls were negative. As this assay is based on PERV antigen derived from infected human cells, it clearly has the capacity to detect a serologic response towards PERV variants that have zoonotic potential and will allow for the accurate determination of PERV-specific seroreactivity in porcine xenograft recipients.

Redox regulation of cellular activation.

Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of "redox regulation" is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.

The promiscuous IL-2/IL-15 receptor: a target for immunotherapy of HTLV-I-associated disorders.

Human T-cell lymphotrophic virus I (HTLV-I)-encoded tax plays a role in the early phases of HTLV-I-induced disease by deregulating the expression of the genes that encode interleukin-2 (IL-2) and the multisubunit (IL-2R alpha, IL-2R beta, and IL-2R gamma) IL-2 receptor (IL-2R). However, later in the course of the disease adult T-cell leukemia (ATL), cells no longer produce IL-2 yet continue to express the IL-2R. During studies to define the pathogenic mechanisms that underlie this IL-2-independent proliferation, we defined a cytokine designated IL-T/IL-15 that stimulates T-cell proliferation and requires the expression of IL-2R beta and IL-2R gamma for its action. To exploit the fact that IL-2Rs are present on abnormal T cells in patients with tropical parasitic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and ATL but not on normal resting cells, different forms of IL-2R-directed therapy have been initiated. Unmodified humanized anti-Tac is being used to treat patient with TSP/HAM. To enhance its effector function for the treatment of ATL anti-Tac was armed with alpha- and beta-emitting radionuclides. In a clinical trial with 90Y-anti-Tac at the doses used (5, 10, and 15 mCi), 9 of the 18 patients with ATL underwent a partial or sustained complete remission. Thus the clinical application of IL-2R-directed therapy using a humanized monoclonal antibody or that antibody armed with radionuclides provides a new perspective for the treatment of autoimmune disorders such as TSP/HAM and certain neoplastic diseases including ATL.

The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.

Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine.

The retroviruses human T-cell lymphotrophic virus-I (HTLV-I) and HTLV-III/LAV (lymphadenopathy-associated virus) are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV). Because HTLV-III infects only humans and chimpanzees, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT) is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.

Changes in the fundus caused by polycythaemia.

Following infection by human T cell lymphotrophic virus-I (HTLV-I), high frequencies of polyclonal Tax11–19-reactive CD8⁺ T cells can be detected in the peripheral blood. To investigate whether there are differences in the effector functions of these cells, we generated a panel of Tax11–19-reactive T cell clones by single cell sorting of HLA-A2/Tax11–19 tetramer binding CD8⁺ T cells followed by repeated stimulation with PHA and IL-2. Examination of the TCRs revealed 17 different T cell clones with unique clonal origins. Nine representative CD8⁺ T cell clones showed a similar cytotoxic dose-response activity against Ag-pulsed target cells, even though they express different TCRs. This cytotoxic effector function was not influenced by the engagement of either CD28 or CD2 costimulatory molecules. In contrast to the cytotoxic activity, qualitatively different degrees of proliferative response and cytokine secretion were observed among T cell clones of different clonal origin. The induction of proliferation and cytokine secretion required the engagement of costimulatory molecules, particularly CD2-LFA-3 interaction. These results indicate that functionally diverse, polyclonal CTL populations can be activated specific to a single immunodominant viral epitope; they can manifest virtually identical cytotoxic effector function but have marked differences in proliferation and cytokine secretion.