Human T-cell Leukemia Virus Type 1 Carriers Research Articles

Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey.

Adult T‐cell leukemia–lymphoma (ATL) is a mature T‐cell malignancy associated with human T‐cell leukemia virus type 1 (HTLV‐1) infection. Japan is the most endemic country for HTLV‐1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV‐1 carriers spread from endemic areas to non‐endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one‐third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV‐1 carrier status are needed.

Hematopoietic Stem Cell Infected with HTLV-1 Functions As a Viral Reservoir In Vivo

▪Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of a malignant disease of peripheral CD4+ T cells called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although major target of HTLV-1 is CD4+ T cells, other hematopoietic cells such as CD8+ T cells and monocytes are also infected with HTLV-1. Since the receptors of HTLV-1 are glucose transporter 1 and neuropilin 1, which are found on various cell surfaces, it is possible that HTLV-1 infects various hematopoietic cells and hematopoietic stem cells (HSCs). However, the previous studies could not detect HTLV-1 in HSCs. To assess the distribution of infected cells and expression of viral genes in various tissues, a nonhuman primate model, Japanese macaques (JMs) infected with simian T-cell leukemia virus type 1 (STLV-1) was utilized in this study. STLV-1 is a close relative of HTLV-1, and the dynamics of viral replication and proliferation of infected cells are very similar to each other. Indeed, STLV-1 caused malignant lymphomas in STLV-1 infected monkeys. Therefore, STLV-1 infected JMs are good models of HTLV-1 carriers. Using this model, we first analyzed transcription level of two viral genes, tax and STLV-1 bZIP factor, in multiple tissues, and found that tax was highly expressed in bone marrow compared to other tissues. Since Tax is a potent activator of viral transcription, this result suggested that viral replication occurred in bone marrow. To evaluate which cells express Tax in bone marrow, we performed flow cytometric analysis of bone marrow mononuclear cells from STLV-1 infected monkeys, and found that not only CD4+ T cells but also non T cells (CD3 negative cells) expressed Tax. To determine whether hematopoietic stem cells are infected with HTLV-1, we next performed highthroughput sequencing of HTLV-1 integration sites in multiple cell lineages using a next generation sequencer. Since HTLV-1 is randomly integrated into genome of infected cells, and each infected cell can proliferate clonally, we can interpret that cells sharing same integration sites are derived from the same precursor cell. Blood samples from patients with HAM/TSP were separated into five cell types: CD4+ T cells, CD8+ T cells, B cells, monocytes, and neutrophils. Integration sites of HTLV-1 provirus were analyzed by next generation sequencing using different chips for each cell type in order to avoid cross contamination between the samples. The results showed that some of these cells have same integration sites between different cell types. More than 40 percent of HTLV-1 infected B cells, monocytes and neutrophils had shared the same integration sites, suggesting that HSCs in the HAM/TSP patients were infected with HTLV-1. Importantly, most HTLV-1 infected CD4+ T cells and CD8+ T cells had independent integration sites, while some of them shared the same integration sites with non T cell subsets. These results implied that most T-cell clones were generated by de novo infection in the periphery, but a part of infected T cells were derived from infected HSCs. To assess whether HTLV-1 infected HSCs persist in vivo, we again analyzed integration sites in neutrophils from the same HAM/TSP patients after 1 year. About 50 percent of integration sites in HTLV-1 infected neutrophils were detected after 1 year. Considering short lifespan of neutrophils, this result suggests that HTLV-1 infected HSCs could be maintained for at least 1 year in vivo. To visualize HTLV-1 infection in myeloid cells, we performed immunofluorescence staining of neutrophils from HAM/TSP patients. Tax and myeloperoxidase were detected in neutrophils. Finally, we evaluated the significance of infected monocytes in viral transmission. We isolated monocytes from HAM/TSP patients and co-cultured with JET WT35 cell, which is a subline of Jurkat containing a fluorescent reporter of viral infection. The result demonstrated that monocyte from HAM/TSP patients could be a source of infective HTLV-1. In conclusion, our findings suggest that HSCs infected with HTLV-1 survive for long time in vivo, and could be reservoirs of the virus. Since ATL is a difficult disease to cure, further studies are required to understand the nature of HTLV-1 infection. DisclosuresNo relevant conflicts of interest to declare.

O2-8-5 - Possible stimulatory immune checkpoint molecules releasing allows adult T-cell leukemia/lymphoma development

The interleukin (IL)-2 receptor α chain (IL-2Rα, CD25) and CD30 are cell membrane proteins expressed on activated T-cell. High levels of soluble cytokine receptors, soluble IL-2Rα (sIL-2R) and soluble CD30 (sCD30) are detected in the serum of patients with adult T-cell leukemia/lymphoma (ATL), which is a highly aggressive leukemia/lymphoma caused by human T-cell leukemia virus type 1 (HTLV-1) (Nishioka C, Takemoto S, et al. 2005; Porunkuna R, Takemoto S, et al. 2014). Freshly isolated leukemic cells from acute type ATL patients express little CD30 on the surface, and predominantly produce sCD30 (Pornkuna R, Nishioka C, and Takemoto S. 2014). We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers (Takemoto S, et al. 2015). We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sIL-2R and sCD30 concentrations at baseline were significantly higher in cases than in controls (P = 0.009 and P<0.001, respectively). In the univariate logistic regression analysis, a higher sIL-2R (≥546.5 U/mL) or sCD30 (≥30.2 U/mL) was significantly associated with ATL development. Among cases, sIL-2R and sCD30 concentrations tended to increase at the time of diagnosis of aggressive-type ATL, but the concentrations were stable in those developing the smoldering-type. High levels of sIL-2R probably down-regulate the proliferative capability of T cells that encounter tumor cells, and proliferating ATL cells are thought to release sCD30, and excess sCD30 may block CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATL cells from apoptosis. Accordingly, high levels of sIL-2R and sCD30 suggest that impaired tumor surveillance leads to the survival of ATL cells. The interleukin (IL)-2 receptor α chain (IL-2Rα, CD25) and CD30 are cell membrane proteins expressed on activated T-cell. High levels of soluble cytokine receptors, soluble IL-2Rα (sIL-2R) and soluble CD30 (sCD30) are detected in the serum of patients with adult T-cell leukemia/lymphoma (ATL), which is a highly aggressive leukemia/lymphoma caused by human T-cell leukemia virus type 1 (HTLV-1) (Nishioka C, Takemoto S, et al. 2005; Porunkuna R, Takemoto S, et al. 2014). Freshly isolated leukemic cells from acute type ATL patients express little CD30 on the surface, and predominantly produce sCD30 (Pornkuna R, Nishioka C, and Takemoto S. 2014). We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers (Takemoto S, et al. 2015). We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sIL-2R and sCD30 concentrations at baseline were significantly higher in cases than in controls (P = 0.009 and P<0.001, respectively). In the univariate logistic regression analysis, a higher sIL-2R (≥546.5 U/mL) or sCD30 (≥30.2 U/mL) was significantly associated with ATL development. Among cases, sIL-2R and sCD30 concentrations tended to increase at the time of diagnosis of aggressive-type ATL, but the concentrations were stable in those developing the smoldering-type. High levels of sIL-2R probably down-regulate the proliferative capability of T cells that encounter tumor cells, and proliferating ATL cells are thought to release sCD30, and excess sCD30 may block CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATL cells from apoptosis. Accordingly, high levels of sIL-2R and sCD30 suggest that impaired tumor surveillance leads to the survival of ATL cells.

The comparison of the microRNAs profiles as the diagnostic tool between the cutaneous type adult T-cell lymphoma and mycosis fungoides

The sero-prevalence against human T-cell leukemia virus type1 (HTLV-1) were high in the population living at western Japan among worldwide, more than 10% in the particularly area of Ryukyu islands. In the high prevalence area, the phenotypes of tumor cells including CD3, 4, 25 markers, the rearrangement of T-cell receptor and HTLV-1 integration are commonly observed in either patient with cutaneous type ATL and mycosis fungoides occurred in HTLV-1 carrier. We do not have yet the good diagnostic tool to differentiate these patients with very unlike clinical prognosis. That is to say, in the endemic area such as Okinawa prefecture, we must treat and care the patients with CD4+ cutaneous T cell lymphoma of HTLV-1 carrier in some cases using anti-CCR4 antibody or radial chemotherapy without the definite diagnosis. To differentiate them, we compared the expression profile of microRNAs at skin lesions by the exhaustive microRNA microarray, and further tried to determine the distinctive downstream-regulated proteins. Patients were selected from cutaneous type ATL with their representative clinical course and mycosis fungoides with the absence of HTLV-1 antibody. Skin lesions of analyzed 3 cutaneous ATL and 2 mycosis fungoides cases were vastly occupied with the tumor cells. Approximately 2500 of human microRNAs were systematically analyzed, however, their expressions of microRNAs were very similar between cutaneous ATL and mycosis fungoides, and accordingly we could not find out any specific microRNA in each phenotype. In other word, although these cutaneous lymphomas develop from the distinct carcinogenesis mechanisms and have distinctive clinical prognosis, we have no clinically useful technique to distinguish them yet.

Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1); no effective methods have yet been identified to prevent development of ATLL in carriers of HTLV-1. This study investigated the association between cigarette smoking and the risk of ATLL development among Japanese carriers of HTLV-1. This study examined the association between smoking and development of ATLL in a cohort of 1,332 Japanese HTLV-1 carriers aged 40-69years free of ATLL at baseline from two different HTLV-1-endemic areas of Japan. Cox proportional hazards models adjusted for sex, geographic area, age at baseline, and alcohol drinking were used to estimate the effect of cigarette smoking on ATLL development. Between 1993 and 2012, 25 new ATLL cases were identified among these subjects. The overall crude incidence rate for ATLL was 1.08 per 1,000 person-years among HTLV-1 carriers and was higher among male carriers than among female carriers (2.21 vs. 0.74). The risk of ATLL development increased significantly with increasing numbers of cigarettes smoked per day (hazard ratio for every increment of 20 cigarettes, 2.03; 95% confidence interval (CI) 1.13-3.66 overall, 2.07 (95% CI 1.13-3.73) in male carriers). Cigarette smoking may influence ATLL development among HTLV-1 carriers in Japan.

Plasmatic proinflammatory chemokines levels are tricky markers to monitoring HTLV-1 carriers

The human T-cell leukemia virus type 1 (HTLV-1) is present throughout the world and is associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory conditions. The pathogenesis of HAM/TSP involves a chronic inflammatory response in central nervous system (CNS), with the presence of HTLV-1 infected cells and HTLV-1-specific CD8+ lymphocytes. Chemokines may have a role in the infiltration of these cells into the CNS. In this context, the present study analyzed the level of plasmatic chemokines CCL2 (MCP-1), CCL5 (RANTES), IL8 (CXCL8), CXCL9 (MIG), and CXCL10 (IP-10) and HTLV-1 proviral load from peripheral blood in 162 asymptomatic carriers and 136 HAM/TSP patients to determine the differences that be associated with the clinical status of the HTLV-1 infection. The results showed that patients with HAM/TSP have significantly higher levels of IL8 and CXCL9, and that the level of IL8, CXCL9 and CXCL10 was significantly greater in HTLV-1 infected individuals with high (>1%) than those with low proviral load (<1%). However, the levels of the chemokines tested have not showed high sensitivity to discriminate HAM/TSP patients from asymptomatic carriers. In addition, chemokine profiles in asymptomatic carriers and HAM/TSP groups were similar, with no significant increased frequency of higher producers of chemokines in HAM/TSP individuals. Results indicate that the heterogeneity of the individuals in the groups regarding time of infection, duration of disease, proviral load level and other possible confound factors may impair the use of chemokines levels to monitor HTLV-1 carriers in clinical practice. J. Med. Virol. 88:1438-1447, 2016. © 2016 Wiley Periodicals, Inc.

Molecular Pathology of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm of highly pleomorphic lymphoid cells. ATLL is usually widely disseminated, and it is caused by human T-cell leukemia virus type 1 (HTLV-1). It is a disease with a long latency, and affected individuals are usually exposed to the virus very early in life. The cumulative incidence of ATLL is estimated to be 2.5% among HTLV-1 carriers. ATLL cells express CD2, CD3, CD5, CD4, and CD25, as well as CCR4 and FoxP3 of the regulatory T-cell marker. HTLV-1 is causally linked to ATLL, but infection alone is not sufficient to result in neoplastic transformation. A significant finding in this connection is that the Tax viral protein leads to transcriptional activation of many genes, while the HTLV-1 basic leucine zipper factor is thought to be important for T-cell proliferation and oncogenesis. Half of ATLL cases retain the ability to express HTLV-1 Tax, which is a target of HTLV-1-specific cytotoxic T lymphocytes (CTL). An increase in HTLV-1-specific CTL responses is observed in some asymptomatic HTLV-1 carriers. Although HTLV-1-specific CTL are also present in the peripheral blood of ATLL patients, they do not expand sufficiently. We investigated the clinicopathological features and analyzed the staining of Tax-specific CTL and FoxP3. Tax-specific CTL correlated inversely with FoxP3, an increase in the ratio of CD163+ tumor-associated macrophages was associated with worse clinical prognosis, and ATLL cell lines proliferated significantly following direct co-culture with M2 macrophages. Several clinical variants of ATLL have been identified: acute, lymphomatous, chronic, and smoldering. Oligo-array comparative genomic hybridization revealed that genomic loss of 9p21.3 was a significant characteristic of acute-type, but not of chronic-type ATLL. Furthermore, we found that genomic alteration of CD58, which is implicated in immune escape, is more frequently observed in acute than in chronic ATLL. Interestingly, the chronic cases with cell cycle deregulation and disruption of immunosurveillance mechanism were associated with faster progression to acute ATLL. Immune evasion, microenvironment, and genetic alteration are therefore important in the multi-step progression of ATLL lymphomagenesis.

Standardization of Quantitative PCR for Human T-Cell Leukemia Virus Type 1 in Japan: a Collaborative Study.

Quantitative PCR (qPCR) analysis of human T-cell leukemia virus type 1 (HTLV-1) was used to assess the amount of HTLV-1 provirus DNA integrated into the genomic DNA of host blood cells. Accumulating evidence indicates that a high proviral load is one of the risk factors for the development of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, interlaboratory variability in qPCR results makes it difficult to assess the differences in reported proviral loads between laboratories. To remedy this situation, we attempted to minimize discrepancies between laboratories through standardization of HTLV-1 qPCR in a collaborative study. TL-Om1 cells that harbor the HTLV-1 provirus were serially diluted with peripheral blood mononuclear cells to prepare a candidate standard. By statistically evaluating the proviral loads of the standard and those determined using in-house qPCR methods at each laboratory, we determined the relative ratios of the measured values in the laboratories to the theoretical values of the TL-Om1 standard. The relative ratios of the laboratories ranged from 0.84 to 4.45. Next, we corrected the proviral loads of the clinical samples from HTLV-1 carriers using the relative ratio. As expected, the overall differences between the laboratories were reduced by half, from 7.4-fold to 3.8-fold on average, after applying the correction. HTLV-1 qPCR can be standardized using TL-Om1 cells as a standard and by determining the relative ratio of the measured to the theoretical standard values in each laboratory.

Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry.

We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4+ cells from peripheral blood, CADM1−CD7+ (P), CADM1+CD7dim (D) and CADM1+CD7− (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4+ cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (>4 copies/100 cells) had a CADM1+ (D + N) frequency of >10%. AC with 25% < CADM1+ ≤ 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25% < CADM1+ ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.

Incidence of adult T-cell leukemia/lymphoma in nonendemic areas.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm with extremely poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). The distribution of HTLV-1 and the incidence of ATLL in endemic areas have been well described, however, little is known about the incidences and the trends of the disease in nonendemic areas. Recently, studies have shown that the HTLV-1 carriers are increasing in nonendemic areas. Also, the incidence of ATLL seems to be significantly increasing in nonendemic areas suggesting that HTLV-1 carriers have emigrated from endemic areas. These epidemiologic studies indicate the necessity of edification of the disease caused by HTLV-1 and establishing appropriate preventive methods against infection in nonendemic areas.

Prevalence of human T-cell leukemia virus type 1 carrier in Japanese pregnant women in 2013.

Since September 2010, in Japan serological screening for the detection of human T-cell leukemia virus type 1 (HTLV-1) antibodies can be performed for all women during pregnancy with the Japanese public funds for strategies for prevention of HTLV-1 vertical transmission, because Japan, especially Kyushu area, has been reported to be one of the areas of highest prevalence of HTLV-1 in the world [1, 2]. In our previous study [3], we examined the prevalence of HTLV-1 carrier in Japanese pregnant women according to the implement rate and results of HTLV-1 screening and confirmation tests of women who gave births in Japan in 2011. The total rates of positive HTLV-1 screening tests and positive western blot (WB) test in positive screening tests were 0.32% and 49.8%, respectively in 2011. Considering the response rate and the rate of implementation of WB test, the number of HTLV-1 carrier in Japanese pregnant women in 2011 was estimated to be 1,560 (0.15%). In addition, although the number of delivery in Kyushu area was only 14% of Japanese deliveries, 53% of HTLV-1 carrier of Japanese pregnant women was present in Kyushu area. Recently, the migration of Japanese people from Kyushu area to the metropolitan areas has been thought to contribute to a significant decrease of HTLV-1 carriers in Kyushu area and an increase in Kanto (including Tokyo) area in Japan [1, 4]. To confirm this migration in Japanese pregnant women, on December 2014, we requested again 2,544 obstetrical facilities that are members of Japan Association of Obstetricians and Gynecologists (JAOG) to provide information of HTLV-1 tests in pregnant women who delivered at ≥ 22 weeks’ gestation in 2013. A total of 1,356 (53.3%) of 2,544 obstetrical facilities responded and information on a total of 538,167 women, accounting for approximately 54% of all deliveries that occurred in Japan during the study period (approximately 1,001,800 births) was provided. In 2013, the total rates of positive HTLV-1 screening tests and positive WB test in positive screening tests were 0.35% and 50.8%, respectively. Considering the response rate and the rate of implementation of WB test, the number of HTLV-1 carrier in Japanese pregnant women in 2013 was estimated to be 1,780 (0.18%). Table 1 shows the difference in the estimated number of HTLV-1 carrier based on positive WB test by area in Japan between 2011 and 2013. The estimated number of HTLV-1 carrier in 2013 seemed to be more than that in 2011, especially in the northeast and southwest (Kyushu) areas. In addition, 51% of HTLV-1 carrier of Japanese pregnant women was present in Kyushu area, although the number of delivery in Kyushu area was only 13% of Japanese deliveries in 2013. Although the migration of Japanese people from Kyushu area to the metropolitan areas has been supposed to contribute to a significant decrease of HTLV-1 carriers in Kyushu area, the estimated number of HTLV-1 carrier of pregnant women seemed to be increased in Kyushu area. In addition, the estimated rate of HTLV-1 carrier in pregnant women in Kyushu area was still significantly higher than that in the other areas (P < 0.01 by the Chi-square test). Therefore, there are still remaining problems concerning the locality for strategies for prevention of HTLV-1 vertical transmission in Japan.

Genes Related to Antiviral Activity, Cell Migration, and Lysis Are Differentially Expressed in CD4+T Cells in Human T Cell Leukemia Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis Patients

Human T cell leukemia virus type 1 (HTLV-1) preferentially infects CD4(+) T cells and these cells play a central role in HTLV-1 infection. In this study, we investigated the global gene expression profile of circulating CD4(+) T cells from the distinct clinical status of HTLV-1-infected individuals in regard to TAX expression levels. CD4(+) T cells were isolated from asymptomatic HTLV-1 carrier (HAC) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients in order to identify genes involved in HAM/TSP development using a microarray technique. Hierarchical clustering analysis showed that healthy control (CT) and HTLV-1-infected samples clustered separately. We also observed that the HAC and HAM/TSP groups clustered separately regardless of TAX expression. The gene expression profile of CD4(+) T cells was compared among the CT, HAC, and HAM/TSP groups. The paxillin (Pxn), chemokine (C-X-C motif ) receptor 4 (Cxcr4), interleukin 27 (IL27), and granzyme A (Gzma) genes were differentially expressed between the HAC and HAM/TSP groups, regardless of TAX expression. The perforin 1 (Prf1) and forkhead box P3 (Foxp3) genes were increased in the HAM/TSP group and presented a positive correlation to the expression of TAX and the proviral load (PVL). The frequency of CD4(+)FOXP3(+) regulatory T cells (Treg) was higher in HTLV-1-infected individuals. Foxp3 gene expression was positively correlated with cell lysis-related genes (Gzma, Gzmb, and Prf1). These findings suggest that CD4(+) T cell activity is distinct between the HAC and HAM/TSP groups.

Current status of HTLV-1 carrier in Japanese pregnant women

We examined the current status of human T-cell leukemia virus type 1 (HTLV-1) carrier in Japanese pregnant women, according to the results of HTLV-1 screening and confirmation tests of women who gave birth in Japan in 2011. We requested 2642 obstetrical facilities to provide information of HTLV-1 tests and 71.3% of them responded. Considering the response rate and the rate of implementation of confirmation tests, the number of HTLV-1 carrier in Japanese pregnant women was estimated to be 1620 (0.16%) per year.

P53 dysfunction precedes the activation of nuclear factor-κB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein

Transgenic (Tg) mice expressing Tax, a human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, develop mature T-cell leukemia/lymphoma. The leukemic cells in Tg mice expressing Tax show p53 dysfunction and nuclear factor-κB (NF-κB) activation, similar to that seen in adult T-cell leukemia/lymphoma (ATLL) cells from patients infected with HTLV-1. However, it is unclear when these effects occur in HTLV-1 carriers during the development of ATLL. Here, we examined p53 function and NF-κB activity before the onset of leukemia in Tax-expressing Tg (Tax-Tg) mice between 4 and 25 months of age. At 4-10 months of age, 71% of mice showed p53 inactivation, without evidence for NF-κB activation, even though tax expression was consistent from 4 to 25 months of age. The decline in p53 function resulted from decreased p53 accumulation after DNA damage. From 11 months of age onward, 75% of mice showed p53 dysfunction and 37.5% showed constitutive NF-κB activation with the components of p50 and RelB. An NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-κB activity (i.e. p50/RelB) but did not restore p53 function. In vivo, treatment with DHMEQ until 24 months of age prevented the onset of T-cell leukemia in Tax-Tg mice. These results suggest that the Tax-induced decline in p53 function, which is independent of NF-κB activation in the early stage, might be the first stage in the onset of ATLL. NF-κB activity is involved in the later stages of ATLL onset.

Development of peripheral T-cell lymphoma not otherwise specified in an HTLV-1 carrier

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) after a long latency period of about 60 years. As the mature T-cell neoplasms that emerge in patients infected with HTLV-1 are often ATL, T-cell neoplasms developing in such patients tend to be diagnosed simply as ATL without further investigation. However, not all T-cell neoplasms that develop in HTLV-1-infected cases are ATL. Mature T-cell malignancies other than ATL should be carefully excluded in patients infected with HTLV-1, as these sometimes closely resemble ATL in their clinical, morphological, and histological features. Here, we present a case of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in an HTLV-1 carrier. Confirmation of monoclonal integration of the virus with Southern blotting leads to a definite diagnosis of ATL. Although we did not detect the monoclonal integration band of HTLV-1 in this case, the high HTLV-1 proviral load complicated the diagnosis. Multicolor flow cytometric analysis clearly showed that HTLV-1 was not integrated in the tumor cells, and facilitated discrimination of PTCL-NOS from ATL.

Lung miliary micro‐nodules in human T‐cell leukemia virus type I carriers

Human T-cell leukemia virus type 1 (HTLV-1) carriers are rarely subject to inflammatory disorders in multiple organs, other than the well-known complication, adult T-cell leukemia/lymphoma (ATLL). HTLV-1 associated bronchiolo-alveolar disorder (HABA) has been proposed as an immune mediated pulmonary reaction seen rarely in HTLV-1 carriers. The reported clinico-pathological patterns of HABA are diffuse panbronchiolitis (DPB) and lymphoid interstitial pneumonia (LIP). We here report three cases of HTLV-1 carriers showing miliary micro-nodules throughout both lungs. Microscopic examination in the video assisted thoracic surgery biopsies demonstrated that all cases had multiple discrete micro-nodules which consisted of marked lymphoid infiltration, granulomas, eosinophils and a few foci of necrosis inside the granuloma. No findings indicating ATLL, other neoplastic conditions, infection or interstitial pneumonia, including DPB and LIP, were present following panels of special staining and immunohistochemical examinations. Two patients improved without treatment within one month, with no evidence of recurrence after 7 years. One patient showed slow deterioration of lung reticular shadows in spite of a low dose corticosteroid therapy (prednisolone 10 mg/day). We believe these cases may be a newly recognized variant of HABA.

HTLV-1-associated inflammatory myopathies: Low proviral load and moderate inflammation in 13 patients from West Indies and West Africa

BackgroundThe Human T-cell Leukemia Virus type 1 (HTLV-1) is the causative agent of several inflammatory diseases, including HTLV-1-associated inflammatory myopathies (HAIM). Little is known about the virological and immunological characteristics of this viral disease. ObjectivesTo characterize the histological and virological features of HAIM patients, in order to better understand the pathogenetic mechanisms and unravel new biological markers of this disease. Study designWe conducted a retrospective study on 13 patients with HAIM, based on blood and muscle samples. We included blood samples from HTLV-1-infected individuals without myopathy as controls. Muscle biopsies were used for a broad immunohistological evaluation of tissue damage and inflammation, as well as identification of infected cells through in situ hybridization. DNA extracted from patients’ PBMC was used to identify the virus genotype by sequencing and to assess the proviral load by quantitative PCR. Anti-viral antibodies in plasma samples were titrated by indirect immunofluorescence. ResultsPatients originate from HTLV-1 endemic areas, the West Indies and West Africa. Histological alterations and inflammation in patients muscles were mostly moderate, with classical features of idiopathic myositis and rare HTLV-1-infected infiltrating cells. In all patients, HTLV-1 belonged to the A subtype, transcontinental subgroup. Anti-HTLV-1 antibodies titers were high, but the proviral load was not elevated compared to asymptomatic HTLV-1 carriers. ConclusionWe show here that muscle inflammation is moderate in HAIM, and accompanied by a low HTLV-1 proviral load, suggesting that the pathogenetic events do not exactly mirror those of other HTLV-1-associated inflammatory diseases.

HTLV-1: Recent topics in epidemiologic, basic and clinical research

Human T-cell leukemia virus type 1 (HTLV-1) belongs to Delta Retorviridae, and induces a malignancy of CD4+CD25+ T-cells, adult T-cell leukemia (ATL), and several chronic inflammatory diseases, such as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1 uveitis. A nationwide survey of HTLV-1-infected subjects, which was recently conducted by Japanese government, revealed that the numbers of HTLV-1 carriers and patients with HTLV-1-associated diseases have not decreased much over the last two decades in Japan. In contrast, novel findings on HTLV-1 dynamics in vivo and molecular mechanisms of its pathogenesis are accumulating by detailed analysis of newly identified viral and cellular factors, novel technologies such as next-generation sequencing, and appropriate animal models for HTLV-1 research. In this review, we summarize the recent progress of HTLV-1 research.

A novel mechanism of HTLV-1-associated mylopathytropical spastic paraparesis (HAMTSP) pathogenesis

Event Abstract Back to Event A novel mechanism of HTLV-1-associated mylopathytropical spastic paraparesis (HAMTSP) pathogenesis Abbas Pishdadian1, Jalil Tavakkol Afshari2* and Mohsen Foroughi Pour3 1 Mashad University of Medical Sciences, Bu-Ali Research Institute, Immunology Research Center, Iran 2 Mashhad University of Medical Sciences, Immunology Research Institute, Iran 3 Mashhad University of Medical Sciences, Neurology Department, Ghaem Hospital, Iran Introduction Human T cell leukemia virus type 1 (HTLV-1), is etiologic agent of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), a slowly progressive neurologic disease. Soluble form of Fas (sFas) molecule implicate in Fas signaling, suggesting a role in some pathogenesis. We hypothesized that existence of sFas might cause partial resistance against Fas-mediated apoptotsis seen in HAM/TSP patients. Methods and Materials Twenty people of each HAM/TSP patient, asymptomatic HTLV-1 carrier (AC) and healthy volunteer groups, who were followed at HTLV-1-Clinic of Ghaem Hospital, were chosen. Gene expression (using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)) and serum protein level (using a highly sensitive enzyme-linked immunosorbent assay (ELISA)) of sFas in each three subject groups were evaluated. Results The Mean sFas serum level in patients (0.389 ng/ml) was significantly higher than healthy individuals (0.131 ng/ml) (p<0.05). There were no significant differences between HAM/TSP patients and ACs (0.253 ng/ml) (p=0.17) and also no significant differences between AC and healthy groups (p=0.16). Although the mean sFas gene expression in patients (0.456) was higher than both carriers (0.304) (p=0.35) and control individuals (0.221) (p=0.15), and also in carriers was higher than controls (p=0.6), but these differences were not statistically significant. There was no significant difference and correlation between sFas serum level and gene expression in each three subject groups. Conclusion These results suggest that sFas may play an important role in the pathogenesis of HAM/TSP and that serum sFas may be related to clinical activity in HAM/TSP patients, but the source of the elevated serum sFas in HTLV-1 infected patients remains unclear. Keywords: Fas/Fas L, HTLV-1, soluble Fas, RT-PCR, HAM/TSP patients, serum level sFas Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Host-pathogen interactions Citation: Pishdadian A, Tavakkol Afshari J and Foroughi Pour M (2013). A novel mechanism of HTLV-1-associated mylopathytropical spastic paraparesis (HAMTSP) pathogenesis. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01179 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 Jul 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Jalil Tavakkol Afshari, Mashhad University of Medical Sciences, Immunology Research Institute, Mashhad, Khorasan Razavi, 9196773117, Iran, tavakolaj@mums.ac.ir Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Abbas Pishdadian Jalil Tavakkol Afshari Mohsen Foroughi Pour Google Abbas Pishdadian Jalil Tavakkol Afshari Mohsen Foroughi Pour Google Scholar Abbas Pishdadian Jalil Tavakkol Afshari Mohsen Foroughi Pour PubMed Abbas Pishdadian Jalil Tavakkol Afshari Mohsen Foroughi Pour Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Impact of Human T Cell Leukemia Virus Type 1 in Living Donor Liver Transplantation

Human T cell leukemia virus type 1 (HTLV-1) is an endemic retrovirus in southwestern Japan, which causes adult T cell leukemia (ATL) or HTLV-1 associated myelopathy in a minority of carriers. Here, we investigated the impact of HTLV-1 status in living donor liver transplantation (LDLT). Twenty-six of 329 (7.9%) HTLV-1 carriers underwent primary LDLT. One recipient negative for HTLV-1 before LDLT received a graft from an HTLV-1 positive donor. Eight donors were HTLV-1 positive. Twenty-seven recipients (13 male and 14 female; mean age 52.5 years) were reviewed retrospectively. ATL developed in four recipients who ultimately died. The intervals between LDLT and ATL development ranged from 181 to 1315 days. Of the four ATL recipients, two received grafts from HTLV-1 positive donors and two from negative donors. The 1-, 3- and 5-year HTLV-1 carrier survival rates were 91.3%, 78.3% and 66.3%, respectively. Fulminant hepatic failure as a pretransplant diagnosis and a pretransplant MELD score ≥ 15 was identified as risk factors for ATL development in this study (p = 0.001 and p = 0.041, respectively). In conclusion, LDLT can be performed for HTLV-1 positive recipients. However, when fulminant hepatic failure is diagnosed, LDLT should not be performed until further studies have revealed the mechanisms of ATL development.