Human T-cell Leukemia Virus Infection Research Articles

Identification of Potential Key Genes Linked to Gender Differences in Bladder Cancer Based on Gene Expression Omnibus (GEO) Database.

Growing evidence strongly indicates pivotal roles of gender differences in the occurrence and survival rate of patients with bladder cancer, with a higher incidence in males and poorer prognosis in females. Nevertheless, the molecular basis underlying gender-specific differences in bladder cancer remains unknown. The current study has tried to detect key genes contributing to gender differences in bladder cancer patients. The gene expression profile of GSE13507 was firstly obtained from the Gene Expression Omnibus (GEO) database. Further, differentially expressed genes (DEGs) were screened between males and females using R software. Protein-protein interactive (PPI) network analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Kaplan-Meier survival analyses were also performed. We detected six hub genes contributing to gender differences in bladder cancer patients, containing IGF2, CCL5, ASPM, CDC20, BUB1B, and CCNB1. Our analyses demonstrated that CCNB1 and BUB1B were upregulated in tumor tissues of female subjects with bladder cancer. Other genes, such as IGF2 and CCL5, were associated with a poor outcome in male patients with bladder cancer. Additionally, three signaling pathways (focal adhesion, rheumatoid arthritis, and human T-cell leukemia virus infection) were identified to be differentially downregulated in bladder cancer versus normal samples in both genders. Our findings suggested that gender differences may modulate the expression of key genes that contributed to bladder cancer occurrence and prognosis.

FHIT as a biomarker for early screening of adult T-cell leukemia.

Adult T-cell leukemia (ATL) is an incurable leukemia deriving from human T-cell leukemia virus (HTLV-I) infected cells. In our most recent study, we discovered that methylation of the tumor suppressor, fragile histidine triad gene (FHIT), exists in the majority of acute and chronic ATL patients. Methylation was seen in non-tumorigenic cells, in cells with low levels of HTLV-I integrated DNA, in longitudinal samples from HTLV-I carriers, in a percentage of HTLV-I carriers, and in direct descendants of ATL patients. Overall, this suggests that FHIT methylation is likely present in patients, prior to HTLV-I infection, and predisposes HTLV-I carriers to ATL development. In this commentary we discuss the importance of developing diagnostic tools for the early detection of FHIT methylation and the possibility that prior FHIT methylation may predispose any individual to the development of cancer.

Weighted gene coexpression network reveals downregulation of genes in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a serious lung disease observed in premature infants, known to cause considerable morbidity and mortality. Its prognosis is influenced by a complex network of genetic interactions. In this study, we determined the potential key factors in the pathogenesis of this condition. We constructed scale-free gene coexpression network using weighted gene coexpression network analysis. The analysis was carried out on the GSE8586 dataset, which contains the expression profiles of umbilical cord tissue homogenates from 20 neonates with BPD and 34 unaffected controls. Our analysis identified one significantly downregulated coexpression module related to the BPD phenotype. It was significantly enriched in genes related to human T-cell leukemia virus infection and the mitogen-activated protein kinase pathway. In this module, the expression of the following four hub genes in infants with BPD was significantly decreased: Fos proto-oncogene (FOS), BTG antiproliferation factor 2 (BTG2), Jun proto-oncogene (JUN), and early growth response protein 1 (EGR1). The downregulation of these hub genes was verified in clinical samples derived from blood and umbilical cord tissue. The decreased expression of FOS, BTG2, JUN, and EGR1 is associated with BPD and, therefore, could be used as biomarkers to diagnose early BPD.

Flow cytometric methodology for the detection of de novo human T-cell leukemia virus -1 infection in vitro: A tool to study novel infection inhibitors

Methodology to detect and study de novo human T-cell leukemia virus (HTLV)-1 infection is required to further our knowledge of the viruses’ mechanisms of infection and to study potential therapeutic interventions. Whilst methodology currently exists, utilisation of an anti-Tax antibody to detect de novo Tax expression in permissive cells labelled with cell tracker allowing for the detection by flow cytometry of new infection after co-culture with donor cell lines productively infected with HTLV-1 is an alternative strategy. Using this methodology, we have been able to detect de novo infection of the T cell line HUT78 following co-culture with the productively infected HTLV-1 donor cell line MT-2 and to confirm that infection can be effectively blocked with well characterised infection inhibitors. This methodology will benefit experimental studies examining HTLV infection in vitro and may aid identification of therapeutic agents that block this process.

Evidence of New Endemic Clusters of Human T-Cell Leukemia Virus (HTLV) Infection in Bahia, Brazil.

BackgroundSalvador, Bahia (northeastern Brazil), has been identified as the epicenter of Human T-cell leukemia virus Human T-cell leukemia virus (HTLV) type 1 infection in the country. This study aims to estimate the rate of HTLV infection and the geographical distribution of this virus in this state.MethodsAll HTLV tests (chemiluminescence/ELISA assays/Western Blotting) performed in the Central Laboratory of Public Health of Bahia (LACEN) from 2004 to 2013 were included. Data was extracted from LACEN’s database using high volume extract, transformation and load throughput. Infection rate was expressed as the number of infected individuals per 100,000 inhabitants considering municipalities grouped in microregions and/or mesoregions as the unit of analysis.ResultsA total of 233,876 individuals were evaluated. Individuals were from 394 out of 417 municipalities of Bahia (94.5%). HTLV chemiluminescence/ELISA assay was found to be reactive for 3,138 individuals from whom 2,323 had WB results (1,978 positives, 62 negative and 282 indeterminate). Out of 1978 reactive samples, 1,813 (91.7%) were positive for HTLV-1, 58 (2.9%) for HTLV-2 and 107 (5.4%) were for both HTLV-1 and HTLV-2. The cumulative mean rate of HTLV-positive cases in Bahia was 14.4 per 100,000 inhabitants. Three microregions presented rates >20 HTLV-positive cases/100,000 inhabitants: Barreiras (24.83 cases per 100,000 inhabitants), Salvador (22.90 cases per 100,000 inhabitants), and Ilhéus-Itabuna (22.60 cases per 100,000 inhabitants).ConclusionHTLV infection is disseminated in the state of Bahia, with an overall moderate rate of infection. Further studies should be conducted to characterize the epidemiological and clinical profile of HTLV-infected individuals better and to propose effective prevention measures.

Prevalence of Human T-cell Leukemia Virus Antibodies among Young Females Attending a Large Medical Diagnostic Laboratory in Neyshabour, Northeast of Iran, During 2011 to 2015

Background: Human T-Cell Leukemia Virus (HTLV) infection is endemic in Neyshabour, and even higher than other cities. Objectives:: The aim of this investigation was to determine the prevalence of HTLV antibodies among young females attending a large medical diagnostic laboratory in Neyshabour, during 2011 to 2015. Methods: The researchers established this study by data, which were collected from the surveillance system. Based on HTLV-1 and HTLV-2 ELISA kit instruction, 5724 females were evaluated. Variables were age, year, and season. Data were analyzed by the SPSS software. Results: According to the Enzyme Linked Immunosorbent Assay (ELISA) results, 117 (2.04 %) young females indicated evidence of antibodies to HTLV-1 and HTL -2. Most infected young females were aged 38 to 39 years (4.16%) and according to annual prevalence, the highest rates were found in 2012. Also, most infected young females had referred in October (3.16%). Conclusions: The data obtained suggests that Neyshabour is a high endemic city of HTLV infected young females. Making them aware seems to be vital in avoiding transfer of HTLV infection, especially to the next generation. However, further investigations like population-based studies are required to confirm these results

Human T Cell Leukemia Virus Envelope Binding and Virus Entry Are Mediated by Distinct Domains of the Glucose Transporter GLUT1

The glucose transporter GLUT1, a member of the multimembrane-spanning facilitative nutrient transporter family, serves as a receptor for human T cell leukemia virus (HTLV) infection. Here, we show that the 7 amino acids of the extracellular loop 6 of GLUT1 (ECL6) placed in the context of the related GLUT3 transporter were sufficient for HTLV envelope binding. Glutamate residue 426 in ECL6 was identified as critical for binding. However, binding to ECL6 was not sufficient for HTLV envelope-driven infection. Infection required two additional determinants located in ECL1 and ECL5, which otherwise did not influence HTLV envelope binding. Moreover the single N-glycosylation chain located in ECL1 was not required for HTLV infection. Therefore, binding involves a discrete determinant in the carboxyl terminal ECL6, whereas post-binding events engage extracellular sequences in the amino and carboxyl terminus of GLUT1.

Pathogenesis and treatment of human T-cell leukemia virus infection.

The pathogenesis of human T-cell leukemia virus (HTLV)-induced adult T-cell leukemia-lymphoma (ATLL) was explored using an infectious molecular viral clone and a transgenic mouse model. Activation of nuclear factor-kappaB by the HTLV transcriptional transactivator protein Tax was found to be important for lymphocyte immortalization and tumorigenesis. Interferon-gamma regulates tumor development owing primarily to angiostatic effects. Translational clinical studies of chemotherapy, interferon-alpha, and nucleoside reverse transcriptase inhibitors have also assisted in identifying the pathogenic features of ATLL.

The Ubiquitous Glucose Transporter GLUT-1 Is a Receptor for HTLV

The human T cell leukemia virus (HTLV) is associated with leukemia and neurological syndromes. The physiopathological effects of HTLV envelopes are unclear and the identity of the receptor, present on all vertebrate cell lines, has been elusive. We show that the receptor binding domains of both HTLV-1 and -2 envelope glycoproteins inhibit glucose transport by interacting with GLUT-1, the ubiquitous vertebrate glucose transporter. Receptor binding and HTLV envelope-driven infection are selectively inhibited when glucose transport or GLUT-1 expression are blocked by cytochalasin B or siRNAs, respectively. Furthermore, ectopic expression of GLUT-1, but not the related transporter GLUT-3, restores HTLV infection abrogated by either GLUT-1 siRNAs or interfering HTLV envelope glycoproteins. Therefore, GLUT-1 is a receptor for HTLV. Perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT-1 are likely to contribute to HTLV-associated disorders.

Assignment of the possible HTLV receptor gene to chromosome 17q21-q23.

We have determined the HTLV (Human T-cell leukemia virus) receptor localization more precisely on the human chromosome 17. Based on the fact that HTLV infection induces syncytium formation of infected cells as a result of interaction between the viral envelope and viral receptor, we performed the sensitive biological assay using recombinant vaccinia expression system. Our results from the induced syncytium pattern of the somatic hybrid cell lines with different deletions indicated that the HTLV receptor gene may reside from q21 to q23 on the long arm of the human chromosome 17.

Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo

Human T-cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. We examined whether HTLV could productively infect human hematopoietic progenitor cells. CD34+ cells were enriched from human fetal liver cells and cocultivated with cell lines transformed with HTLV-1 and -2. HTLV-1 infection was established in between 10 and >95% of the enriched CD34+ cell population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag expression was also detected in infected hematopoietic progenitor cells. HTLV-1-infected hematopoietic progenitor cells were cultured in semisolid medium permissive for the development of erythbroid (BFU-E), myeloid (CFU-GM), and primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences were detected in colonies of all hematopoietic lineages; furthermore, the ratio of HTLV genomes to the number of human cells in each infected colony was 1:1, consistent with each colony arising from a single infected hematopoietic progenitor cell. Severe combined immunodeficient mice engrafted with human fetal thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1-infected T cells or enriched populations of CD34+ cells established viral infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice with the greatest HTLV-1 proviral burdens showed increased expression of the CD25 marker and the interleukin 2 receptor alpha chain and perturbation of CD4+ and CD8+ thymocyte subset distribution profiles. Hematopoietic progenitor cells and thymuses may be targets for HTLV infection in humans, and these events may play a role in the pathogenesis associated with infection.

HTLV infection among Italian intravenous drug users and North African subjects detected by the polymerase chain reaction and serological methods

Six hundred intravenous drug users (IVDUs) and two hundred North Africans were screened for human T-cell leukemia virus (HTLV) antibodies using several serological methods. Eighteen of the eighty-two HTLV-seropositive individuals were also tested by the polymerase chain reaction-DNA enzyme immunoassay (PCR-DEIA), a non-isotopic method of immunoenzymatic detection of the amplified DNA. Of these eighteen subjects, eight IVDUs were found to be HTLV-II-positive by the PCR-DEIA, whereas all of the eighteen subjects were negative for HTLV-I. Western blot (WB) confirmed six of the eight HTLV-positive subjects, while the results of the remaining two were indeterminate. The results confirmed the PCR-DEIA as a rapid and an efficient method of discriminating between HTLV-I and HTLV-II infection, whereas serological tests, including the WB, have limitations in terms of specificity and sensitivity. Moreover, this study showed a higher frequency of HTLV seroreactivity in the Italian IVDU population than in previous studies and confirmed that HTLV-II is more frequent than HTLV-I in this population.

Prevalence of infection by human T-cell leukemia virus types I and II in southern Spain

To assess the spread of human T-cell leukemia virus (HTLV) type I and II in different population groups at potential risk of infection in Spain, a total of 756 subjects were studied: 453 belonging to groups at risk for retrovirus infection, 255 with diseases potentially linked to HTLV-I/II infection and 48 immigrants from endemic areas. An HTLV-I viral-lysate enzyme immunoassay (EIA) with a recombinant transmembrane envelope protein incorporated was used to screen serum samples. Reactive specimens were confirmed by Western blot strips spiked with recombinant proteins that differentiated HTLV-I from HTLV-II. Infection was then verified by the polymerase chain reaction (PCR). Serum samples from 19 of the 756 subjects analyzed (2.5%) were reactive for HTLV by EIA. One of these was from an intravenous drug user (IVDU) in whom HTLV-II infection was confirmed by Western blot and PCR; a specimen from another IVDU showed Western blot reactivity for both retroviruses, but PCR results were negative. Lastly, Western blot confirmed the presence of HTLV in one of the immigrant subjects. Western blot did not verify HTLV infection in the remaining 16 cases, indicating a high rate of nonspecific anti-HTLV reactivity when a second-generation EIA screening test was applied. These results suggest that HTLV is present in Spain among populations at high risk for HTLV, although at a very low rate and restricted to intravenous drug users and individuals immigrating from endemic areas.

Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I.

The human T-cell leukemia virus type I Tax protein trans-activates several cellular genes implicated in T-cell replication and activation. To investigate its leukemogenic potential, Tax was targeted to the mature T-lymphocyte compartment in transgenic mice by using the human granzyme B promoter. These mice developed large granular lymphocytic leukemia, demonstrating that expression of Tax in the lymphocyte compartment is sufficient for the development of leukemia. Furthermore, these observations suggest that human T-cell leukemia virus infection may be involved in the development of large granular lymphocytic leukemia.

Hypercalcemia, parathyroid hormone-related protein expression and human T-cell leukemia virus infection.

Adult T-cell leukemia (ATL) associated with HTLV-1 infection is characterized by the development of hypercalcemia in over two thirds of patients. Dysregulation of cellular gene transcription by viral proteins is an emerging paradigm for molecular pathogenesis of disease. A recent example is the parathyroid hormone-related protein (PTHrP) gene, which has been implicated in the hypercalcemia of ATL, and is transactivated by the HTLV-1 tax and HTLV-11 tax proteins. PTHrP is expressed at high levels in leukemia cells derived from ATL patients, as well as in asymptomatic HTLV-1 positive carriers. This article reviews the interaction of the HTLV-1 transcriptional regulator tax with the PTHrP promoter. Tax mediates its effects on PTHrP via cellular transcription factors AP-2 and AP-1, and transactivation via an AP-2 motif represents a novel interaction of tax with a cellular transcription factor.

Infection with human T-lymphotropic viruses leads to constitutive expression of leukemia inhibitory factor and interleukin-6

Leukemia inhibitory factor (LIF), similar to interleukin-6 (IL-6), is a glycoprotein growth factor and differentiation regulator that has pleiotropic activity in several cellular systems. Recent reports of constitutive IL-6 production from spontaneously proliferating cells from human T-cell leukemia virus (HTLV)-infected individuals led us to examine the expression of IL-6 and LIF during HTLV infection. In vitro infection of peripheral blood lymphocytes with HTLV-I was associated with production of both soluble LIF and IL-6 in conjunction with the increasing HTLV antigen concentration. Northern blot analysis of T-cell lines generated from individuals infected with HTLV-I (MT-2, HuT-102, FS, EG, SP) and HTLV-II (Mo-T, H2A, H2E) demonstrated a marked increase in constitutive expression of LIF and IL-6 transcripts, as compared with uninfected cell lines (HuT-78, Jurkat). The constitutive expression of LIF and IL-6 was independent of presence of IL-2 in the culture medium, as both IL-2-independent (MT-2, HuT-102, SP, Mo-T) and IL-2-dependent (FS, EG, H2A, H2E) cell lines expressed LIF and IL-6 transcripts. Furthermore, LIF and IL-6 RNA expression in an HTLV-I- infected cell line (MT-2) was enhanced by phorbol ester stimulation via mechanisms that appear to be dependent on the posttranscriptional regulatory controls. These results show that both LIF and IL-6 are produced by HTLV-I- and HTLV-II-infected cells, which could potentially alter the transcriptional regulation of HTLV gene expression by inducing certain early response genes.

Infection With Human T-Lymphotropic Viruses Leads To Constitutive Expression of Leukemia Inhibitory Factor and Interleukin-6

Leukemia inhibitory factor (LIF), similar to interleukin-6 (IL-6), is a glycoprotein growth factor and differentiation regulator that has pleiotropic activity in several cellular systems. Recent reports of constitutive IL-6 production from spontaneously proliferating cells from human T-cell leukemia virus (HTLV)-infected individuals led us to examine the expression of IL-6 and LIF during HTLV infection. In vitro infection of peripheral blood lymphocytes with HTLV-I was associated with production of both soluble LIF and IL-6 in conjunction with the increasing HTLV antigen concentration. Northern blot analysis of T-cell lines generated from individuals infected with HTLV-I (MT-2, HuT-102, FS, EG, SP) and HTLV-II (Mo-T, H2A, H2E) demonstrated a marked increase in constitutive expression of LIF and IL-6 transcripts, as compared with uninfected cell lines (HuT-78, Jurkat). The constitutive expression of LIF and IL-6 was independent of presence of IL-2 in the culture medium, as both IL-2-independent (MT-2, HuT-102, SP, Mo-T) and IL-2-dependent (FS, EG, H2A, H2E) cell lines expressed LIF and IL-6 transcripts. Furthermore, LIF and IL-6 RNA expression in an HTLV-I-infected cell line (MT-2) was enhanced by phorbol ester stimulation via mechanisms that appear to be dependent on the posttranscriptional regulatory controls. These results show that both LIF and IL-6 are produced by HTLV-I- and HTLV-II-infected cells, which could potentially alter the transcriptional regulation of HTLV gene expression by inducing certain early response genes.

Prevalence of HTLV infection in the Dominican Republic: association with neurological disease.

The presence of the human T-cell leukemia virus (HTLV) in Dominican blood donors and patients with tropical spastic paraparesis (TSP) was first detected in 1987. To define further the seroprevalence in the country, nearly 4,000 samples from high- and low-risk populations, as well as patients with neurological disease and with leukemia or lymphoma were tested for HTLV antibodies. A 1-2% seropositivity rate was found among the low-risk population, a 2-5% in the high-risk, and at least 87% in those with TSP. A few patients with malignancy also had antibodies to HTLV. An increase in seropositivity with age and a predominance of female seropositive individuals were found. Infectious virus was isolated from TSP patients, prostitutes, and family members of index patients. These data indicate the substantial level of HTLV infection in another Caribbean country and its relation to neurologic disease.

Transmission of human T-cell leukemia virus (HTLV-I) by blood transfusion: demonstration of proviral DNA in recipients' blood lymphocytes.

Human T-cell clones bearing antigens encoded by human T-cell leukemia/lymphoma virus (HTLV-I) were isolated from 6 patients who produced antibodies against HTLV-I after having received anti-HTLV-I-positive blood units containing cell components. On the other hand, it was not possible to isolate clonal cells carrying viral antigens from the recipients who did not produce antibodies. The clonal cell lines had the same surface markers as neoplastic cells of adult T-cell leukemia and had the HLA phenotype of the recipients themselves. Proviral DNA of HTLV-I was demonstrated in each of the clonal cell lines. The site of integration was different in each case even if the clones were derived from the same recipient. These results indicate that blood transfusion can cause persistent HTLV-I infection.

HTLV-I is endemic in southern Italy: detection of the first infectious cluster in a white population.

Human T-cell leukemia virus (HTLV-I) infection is observed among black and Japanese populations in well-delimited endemic spots in association with a high incidence of adult T-cell leukemia (ATL). We present evidence of HTLV-I infection in two ATL patients from southeastern Italy who have not travelled and who have no known relations abroad, and in 8% of non-leukemic controls from the same area. Thus, populations exhibiting HTLV-I infection appear more widespread than supposed up to now.