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1.  High Prevalence of Skin Disorders among HTLV-1 Infected Individuals Independent of Clinical Status 
Human T-cell lymphotropic virus type 1 (HTLV-1) infection can increase the risk of developing skin disorders. This study evaluated the correlation between HTLV-1 proviral load and CD4+ and CD8+ T cells count among HTLV-1 infected individuals, with or without skin disorders (SD) associated with HTLV-1 infection [SD-HTLV-1: xerosis/ichthyosis, seborrheic dermatitis or infective dermatitis associated to HTLV-1 (IDH)].
A total of 193 HTLV-1-infected subjects underwent an interview, dermatological examination, initial HTLV-1 proviral load assay, CD4+ and CD8+ T cells count, and lymphproliferation assay (LPA).
A total of 147 patients had an abnormal skin condition; 116 (79%) of them also had SD-HTLV-1 and 21% had other dermatological diagnoses. The most prevalent SD-HTLV-1 was xerosis/acquired ichthyosis (48%), followed by seborrheic dermatitis (28%). Patients with SD-HTLV-1 were older (51 vs. 47 years), had a higher prevalence of myelopathy/tropical spastic paraparesis (HAM/TSP) (75%), and had an increased first HTLV-1 proviral load and basal LPA compared with patients without SD-HTLV-1. When excluding HAM/TSP patients, the first HTLV-1 proviral load of SD-HTLV-1 individuals remains higher than no SD-HTLV-1 patients.
There was a high prevalence of skin disorders (76%) among HTLV-1-infected individuals, regardless of clinical status, and 60% of these diseases are considered skin disease associated with HTLV-1 infection.
Author Summary
HTLV-1 infection may increase the risk of developing skin disorders. A total of 193 HTLV-1 infected subjects were studied, including asymptomatic carriers and HAM/TSP patients. Of the subjects, 76% had an abnormal skin condition, with a high prevalence both among HTLV-1 asymptomatic carriers and HAM/TSP patients. The most prevalent SD-HTLV-1 was xerosis/acquired ichthyosis (48%), followed by seborrheic dermatitis (28%). Patients with SD-HTLV-1 were older (51 vs. 47 years), had a higher prevalence of myelopathy/tropical spastic paraparesis (HAM/TSP) (75%) and an increased first HTLV-1 proviral load compared with patients without SD-HTLV-1. When excluding HAM/TSP patients, the first HTLV-1 proviral load of SD-HTLV-1 individuals remains higher than no SD-HTLV-1 patients. Thus, skin diseases are highly prevalent among HTLV-1-infected individuals.
PMCID: PMC3820737  PMID: 24244779
2.  High Expression of CD244 and SAP Regulated CD8+ T Cell Responses of Patients with HTLV-I Associated Neurologic Disease 
PLoS Pathogens  2009;5(12):e1000682.
HTLV-I-specific CD8+ T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8+ T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8+ T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-γ production in CD8+ T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8+ T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-γ production in CD8+ T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8+ T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.
Author Summary
Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that persistently infects 20 million people worldwide. The majority of infected individuals are asymptomatic carriers of the virus, but 5–10% of infected people develop either adult T cell leukemia/lymphoma (ATL) or a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is characterized by central nervous system (CNS) inflammation including HTLV-I-specific CD8+ T cells where disease progression and pathogenesis is associated with a dysregulation of antigen-specific CD8+ T cells, although the mechanism of this dysregulation remains to be defined. Here we demonstrate that a signaling lymphocyte activation molecule (SLAM) family of receptors, CD244, was overexpressed on CD8+ T cells of HTLV-I-infected patients than those of healthy normal donors, and that the upregulation of the adaptor protein, SAP, in CD8+ T cells distinguished HTLV-I infected individuals with and without neurologic disease. Both CD244 and SAP were associated with effector functions (high expression of IFN-γ) of CD8+ T cells in patients with HAM/TSP. This finding has important implication for T cell-mediated pathogenesis in human chronic viral infection associated with imbalance of immune function.
PMCID: PMC2779586  PMID: 19997502
3.  Comparison of HTLV-I Proviral Load in Adult T Cell Leukemia/Lymphoma (ATL), HTLV-I-Associated Myelopathy (HAM-TSP) and Healthy Carriers 
Objective(s): Human T Lymphocyte Virus Type one (HTLV-I) is a retrovirus that infects about 10-20 million people worldwide. Khorasan province in Iran is an endemic area. The majority of HTLV-I-infected individuals sustain healthy carriers but small proportion of infected population developed two progressive diseases: HAM/TSP and ATL. The proviral load could be a virological marker for disease monitoring, therefore in the present study HTLV-I proviral load has been evaluated in ATL and compared to HAM/TSP and healthy carriers.
Materials and Methods: In this case series study, 47 HTLV-I infected individuals including 13 ATL, 23 HAM/TSP and 11 asymptomatic subjects were studied. Peripheral blood mononuclear cells (PBMCs) were investigated for presence of HTLV-I DNA provirus by PCR using LTR and Tax fragments. Then in infected subjects, HTLV-I proviral load was measured using real time PCR TaqMan method.
Results: The average age of patients in ATL was 52±8, in HAM/TSP 45.52±15.17 and in carrier’s 38.65±14.9 years which differences were not statistically significant. The analysis of data showed a significant difference in mean WBC among study groups (ATL vs HAM/TSP and carriers P=0.0001). Moreover, mean HTLV-I proviral load was 11967.2 ± 5078, 409 ± 71.3 and 373.6 ± 143.3 in ATL, HAM/TSP and Healthy Carriers, respectively. The highest HTLV-I proviral load was measured in ATL group that had a significant correlation with WBC count (R=0.495, P=0.001). The proviral load variations between study groups was strongly significant (ATL vs carrier P=0.0001; ATL vs HAM/TSP P= 0.0001 and HAM/TSP vs carriers P< 0.05).
Conclusion : The present study demonstrated that HTLV-I proviral load was higher in ATL group in comparison with HAM/TSP and healthy carriers. Therefore, HTLV-I proviral load is a prognostic factor for development of HTLV-I associated diseases and can be used as a monitoring marker for the efficiency of therapeutic regime.
PMCID: PMC3881246  PMID: 24470863
HTLV-I; HAM/TSP; ATL; HTLV-I proviral load
4.  Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers 
Thorax  2005;60(2):138-143.
Background: A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers.
Methods: The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I proviral deoxyribonucleic acid (DNA) load in peripheral blood mononuclear cells (PBMCs) and BAL fluid from HTLV-I carriers was estimated using the quantitative polymerase chain reaction method and the correlation between the lymphocyte number in BAL fluid and the HTLV-I proviral DNA load in PBMCs and BAL fluid was examined.
Results: The percentage of lymphocytes in BAL fluid was increased (>18%) in 11 of 30 HTLV-I carriers although there was no significant difference compared with control subjects. In HTLV-I carriers the lymphocyte number in BAL fluid correlated well with the copy number of HTLV-I proviral DNA in PBMCs. In addition, the copy number of HTLV-I proviral DNA in BAL fluid correlated well with the number of lymphocytes (both CD4+ and CD8+ cells) in BAL fluid.
Conclusions: These findings suggest that pulmonary lymphocytosis can occur in a subset of HTLV-I carriers without HAM/TSP and that the increased HTLV-I proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-I carriers.
PMCID: PMC1747290  PMID: 15681503
5.  HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals 
Retrovirology  2012;9:46.
HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4+ T cells. Infection of CD4+ T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4+ T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4+ T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression.
To investigate the effect of HTLV-1 infection on CD4+ T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs) of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC), 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), 10 patients with adult T-cell leukemia (ATL), and 10 healthy donors. The frequency of FoxP3+ cells in CD4+ T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4+ T cells that were FoxP3+. The CD4+FoxP3+ T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3+ T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the Treg associated molecules CTLA-4 and GITR were decreased in CD4+FoxP3+ T cells. Further we characterized FoxP3+CD4+ T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA−FoxP3low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3+ cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression but also wide variation in FoxP3 expression level among individual cases.
HTLV-1 infection induces an abnormal frequency and phenotype of FoxP3+CD4+ T cells.
PMCID: PMC3403885  PMID: 22647666
6.  HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1) 
PLoS Pathogens  2010;6(11):e1001177.
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1–infected individuals remain asymptomatic carriers (AC) during their lifetime, 2–5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1—SOCS1—was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/β and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-β production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.
Author Summary
Infection with HTLV-1 leads to the development of Adult T cell Leukemia (ATL) or the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1–infected individuals remain asymptomatic carriers (AC) during their lifetime, 2–5% will develop either ATL or HAM/TSP. Using gene expression profiling of CD4+ T lymphocytes from HTLV-1 infected patients, we identified Suppressor of cytokine signaling 1 (SOCS1) as being highly expressed in HAM/TSP and AC patients. SOCS1 expression positively correlated with the high HTLV-1 mRNA load that is characteristic of HAM/TSP patients. SOCS1 inhibited cellular antiviral signaling during HTLV-1 infection by degrading IRF3, an essential transcription factor in the interferon pathway. Our study reveals a novel evasion mechanism utilized by HTLV-1 that leads to increased retroviral replication, without triggering the innate immune response.
PMCID: PMC2973829  PMID: 21079688
7.  High HTLV-1 proviral load, a marker for HTLV-1-associated myelopathy/tropical spastic paraparesis, is also detected in patients with infective dermatitis associated with HTLV-1 
Salvador (BA, Brazil) is an endemic area for human T-cell lymphotrophic virus type 1 (HTLV-1). The overall prevalence of HTLV-1 infection in the general population has been estimated to be 1.76%. HTLV-1 carriers may develop a variety of diseases such as adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). IDH is a chronic and severe form of childhood exudative and infective dermatitis involving mainly the scalp, neck and ears. It has recently been observed that 30% of patients with IDH develop juvenile HAM/TSP. The replication of HTLV-1 has been reported to be greater in adult HAM/TSP patients than in asymptomatic HTLV-1 carriers. In the current study, the proviral load of 28 children and adolescents with IDH not associated with HAM/TSP was determined and the results were compared to those obtained in 28 HTLV-1 adult carriers and 28 adult patients with HAM/TSP. The proviral load in IDH patients was similar to that of patients with HAM/TSP and much higher than that found in HTLV-1 carriers. The high levels of proviral load in IDH patients were not associated with age, duration of illness, duration of breast-feeding, or activity status of the skin disease. Since proviral load is associated with neurological disability, these data support the view that IDH patients are at high risk of developing HAM/TSP.
PMCID: PMC2963476  PMID: 19578703
Infective dermatitis associated with HTLV-1; HTLV-1-associated myelopathy/tropical spastic paraparesis; HTLV-1 proviral loads
8.  The Prevalence of Human T-Lymphotropic Virus Infection among Blood Donors in Southeast China, 2004-2013 
PLoS Neglected Tropical Diseases  2015;9(4):e0003685.
The human T-lymphotropic virus type 1 (HTLV-1) which is associated with the diseases of adult T-cell leukemia/lymphoma, HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP) and HTLV-associated uveitis, can cause transfusion-transmitted infections. Although HTLV screening of blood donors was already routinely performed in developed countries, little is know about the HTLV prevalence among blood donors in developing countries which do not perform HTLV screening, such as China.
Objectives &Aims
To systematically characterize the prevalence of HTLV infection among bloods in southeast China.
A 10-year survey for HTLV prevalence in blood donors was performed in Xiamen, southeast China, during 2004-2013. The HTLV-1/2 of blood donations were screened by enzyme-linked immunosorbent assay, following with confirmation by western blot assay and 9nucleic acid testing. The HTLV-1 prevalences in donors from different cities were calculated. Viral sequences derived from identified HTLV-positive cases were sequenced and analyzed.
Among 253,855 blood donors, 43 were confirmed to be seropositive for HTLV-1 (16.9 per 100,000 95% CI: 12.3-22.8) and none HTLV-2 infection was found. The HTLV-1 prevalence varied significantly in donors from different cities. Donors from cities in Fujian province (24.3 per 100,000, 95%CI: 17.4-33.1) had a significantly higher (p=0.001) HTLV-1 seroprevalence than those who were born in non-Fujian cities (3.4 per 100,000, 95%CI: 0.7-9.8). Among nine cities in Fujian province, the highest prevalence was found in blood donors from Ningde (171.3 per 100,000, 95%CI: 91.3-292.8) which is a coastal city in the northeast of Fujian. Molecular characterization of viral sequences from 27 HTLV-1 carriers revealed 25 were Transcontinental subtype of genotype A and 2 were Japanese subtype of genotype A. Interestingly, 12 of 25 Transcontinental subtype sequences harbored a characteristic L55P mutation in viral gp46 protein, which was only presented in the Transcontinental subtype sequences from Japan and Taiwan but not in that from other countries.
Although China is considered to be a non-endemic region for HTLV, the HTLV-1 prevalence in blood donors is significantly higher in Fujian province, southeast China. A higher prevalence of HTLV-1 in the Fujian may be attributed to endemic foci in the city of Ningde.
Author Summary
The human T-lymphotropic virus type 1 (HTLV-1) which is associated with the diseases of adult T-cell leukemia/lymphoma, tropical spastic paraparesis etc., can cause transfusion-transmitted infections, it also can be transmitted by sex or breastfeeding. Globally, approximately 20 million people are estimated to be infected by HTLV-1, and 90% of them remain asymptomatic carriers during their lives. Previous studies had revealed that Japan, Central and Western Africa, the Caribbean islands and Central and South American were the regions with the highest HTLV-1 prevalence in the world. Little is know about the HTLV prevalence in China. We performed a 10-year blood screening survey to systematically characterize the prevalence of HTLV infection among bloods in Fujian province in southeast China since 2004. The HTLV-1 prevalence in blood donors is significantly higher in southeast China, especially in the northern cities of Fujian province, such as Ningde. Moreover, similar molecular characteristics of prevalent HTLV-1 sequences in southeast China, Taiwan and Japan suggested a same origin of these viruses.
PMCID: PMC4382043  PMID: 25830656
9.  HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP 
PLoS Pathogens  2008;4(3):e1000027.
Human T-lymphotropic virus type 1 (HTLV-1) causes leukaemia or chronic inflammatory disease in ∼5% of infected hosts. The level of proviral expression of HTLV-1 differs significantly among infected people, even at the same proviral load (proportion of infected mononuclear cells in the circulation). A high level of expression of the HTLV-1 provirus is associated with a high proviral load and a high risk of the inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). But the factors that control the rate of HTLV-1 proviral expression remain unknown. Here we show that proviral integration sites of HTLV-1 in vivo are not randomly distributed within the human genome but are associated with transcriptionally active regions. Comparison of proviral integration sites between individuals with high and low levels of proviral expression, and between provirus-expressing and provirus non-expressing cells from within an individual, demonstrated that frequent integration into transcription units was associated with an increased rate of proviral expression. An increased frequency of integration sites in transcription units in individuals with high proviral expression was also associated with the inflammatory disease HAM/TSP. By comparing the distribution of integration sites in human lymphocytes infected in short-term cell culture with those from persistent infection in vivo, we infer the action of two selective forces that shape the distribution of integration sites in vivo: positive selection for cells containing proviral integration sites in transcriptionally active regions of the genome, and negative selection against cells with proviral integration sites within transcription units.
Author Summary
The human leukaemia virus HTLV-1 causes a lifelong infection that cannot be cleared by the immune system. By integrating into the host's DNA, the virus can lie dormant within the cell. The virus can then be reactivated, by processes that are only partly understood, causing the infected cell to multiply and leading to an increase in the quantity of virus in the infected person. In some infected people, the virus is reactivated much faster than in others, and such people are more likely to develop HTLV-1-associated inflammatory diseases such as HAM/TSP, which results in paralysis of the legs. It is not understood what determines this rate of viral reactivation in each person. In this study, we found that integration of HTLV-1 in the host's DNA close to other genes was associated with faster viral reactivation and a higher probability of HAM/TSP. By comparing the viral integration site positions in samples from patients and in cells infected with HTLV-1 in the laboratory, we can identify some of the major forces that allow the virus to persist lifelong whilst avoiding eradication by the immune response.
PMCID: PMC2265437  PMID: 18369476
10.  Humoral immune response to HTLV-1 basic leucine zipper factor (HBZ) in HTLV-1-infected individuals 
Retrovirology  2013;10:19.
Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system.
Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4+ T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients.
This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection.
PMCID: PMC3584941  PMID: 23405908
HTLV-1; Antibody; HAM/TSP; ATL; Asymptomatic carriers; Serum; CSF
11.  High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease 
The Journal of Experimental Medicine  1993;177(6):1567-1573.
The frequencies of human T cell lymphotropic virus type 1 (HTLV-1)- specific CD8+ precursor cytotoxic T lymphocytes (pCTL) were quantitated from lymphocytes obtained from the peripheral blood and cerebrospinal fluid (CSF) of infected individuals with and without HTLV-1-associated neurological disease. An estimate of the pCTL was obtained by separating CD8+ cells, plating these cells in limiting dilution, and testing wells for HTLV-1 specific lysis. Targets consisted of autologous lymphoblastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-1-infected individuals. All HAM/TSP patients (five of five) predominantly recognized HTLV-1 products encoded within the pX region. Lower pCTL to env were demonstrated in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (peptide 11-19, amino acid sequence LLFGYPVYV) was recognized in association with human histocompatibility leukocyte antigen (HLA)-A2 in two HLA-A2 HAM/TSP patients with a high CD8+ pCTL frequency of 1/325 and 1/265, respectively. A second immunodominant region of HTLV-1 tax (peptide 90- 55, amino acid sequence VPYKRIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8+ pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a patient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax- specific peptide 11-19 was also comparable to pCTL from PBL. These results indicate that an extremely high pCTL frequency to HTLV-1 tax- encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.
PMCID: PMC2191033  PMID: 8496677
12.  Multistability in a Model for CTL Response to HTLV-I Infection and Its Implications to HAM/TSP Development and Prevention 
Bulletin of mathematical biology  2009;72(3):681-696.
Human T-cell leukaemia/lymphoma virus type I (HTLV-I) is a retrovirus that has been identified as the causative agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other illnesses. HTLV-I infects primarily CD4+ T cells and the transmission occurs through direct cell-to-cell contact. HAM/TSP patients harbor higher proviral loads in peripheral blood lymphocytes than asymptomatic carriers. Also, HAM/TSP patients exhibit a remarkably high number of circulating HTLV-I-specific CD8+ cytotoxic T lymphocytes (CTLs) in the peripheral blood. While CTLs have a protective role by killing the infected cells and lowering the proviral load, a high level of CTLs and their cytotoxicity are believed to be a main cause of the development of HAM/TSP. A mathematical model for HTLV-I infection of CD4+ T cells that incorporates the CD8+ cytotoxic T-cell (CTL) response is investigated. Our mathematical analysis reveals that the system can stabilize at a carrier steady-state with persistent viral infection but no CTL response, or at a HAM/TSP steady-state at which both the viral infection and CTL response are persistent. We also establish two threshold parameters R0 and R1, the basic reproduction numbers for viral persistence and for CTL response, respectively. We show that the parameter R1 can be used to distinguish asymptomatic carriers from HAM/TSP patients, and as an important control parameter for preventing the development of HAM/TSP.
PMCID: PMC4758685  PMID: 20041353
HTLV-I; HAM/TSP; CD4 T cells; CD8 T cells; Global dynamics; Lyapunov functions
13.  Long Terminal Repeat Circular DNA as Markers of Active Viral Replication of Human T Lymphotropic Virus-1 in Vivo 
Viruses  2016;8(3):80.
Clonal expansion of human T-lymphotropic virus type-1 (HTLV-1) infected cells in vivo is well documented. Unlike human immunodeficiency virus type 1 (HIV-1), HTLV-1 plasma RNA is sparse. The contribution of the “mitotic” spread of HTLV-1 compared with infectious spread of the virus to HTLV-1 viral burden in established infection is uncertain. Since extrachromosomal long terminal repeat (LTR) DNA circles are indicators of viral replication in HIV-1 carriers with undetectable plasma HIV RNA, we hypothesised that HTLV-1 LTR circles could indicate reverse transcriptase (RT) usage and infectious activity. 1LTR and 2LTR DNA circles were measured in HTLV-1 cell lines and peripheral blood mononuclear cells (PBMC) of asymptomatic carriers (ACs) and patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukaemia/lymphoma (ATLL). 1LTR DNA circles were detected in 14/20 patients at a mean of 1.38/100 PBMC but did not differentiate disease status nor correlate with HTLV-1 DNA copies. 2LTR DNA circles were detected in 30/31 patients and at higher concentrations in patients with HTLV-1-associated diseases, independent of HTLV-1 DNA load. In an incident case the 2LTR DNA circle concentration increased 2.1 fold at the onset of HAM/TSP compared to baseline. Detectable and fluctuating levels of HTLV-1 DNA circles in patients indicate viral RT usage and virus replication. Our results indicate HTLV-1 viral replication capacity is maintained in chronic infection and may be associated with disease onset.
PMCID: PMC4810270  PMID: 26985903
long terminal repeat; LTR DNA circles; human T-lymphotropic virus; HTLV; viral replication
14.  IL28B Gene Polymorphism SNP rs8099917 Genotype GG Is Associated with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in HTLV-1 Carriers 
The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860) are associated with HAM/TSP.
The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers) and Group II (93 HAM/TSP patients). The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System.
A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96–4.27) and in rs8099917 genotype GG (OR = 7.61; IC95% = 1.82–31.72).
Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results.
Author Summary
New evidence has shown that the pathogenic mechanism of disease-associated HTLV-1 infection is an impairment of the immunity. More recently, it has been demonstrated that IL28B polymorphisms are more likely to occur among HTLV-1 infected subjects and are associated with higher proviral loads in HTLV-1 carriers. Based on anti-HCV properties exhibited by IL28B, we examined the possibility of an association between IL28B polymorphisms (rs8099917 and rs12979860 SNPs) and HAM/TSP occurrence in a large cohort of HTLV-1-infected subjects in Sao Paulo city, Brazil. This study included 229 HTLV-1-infected subjects classified according to their neurological status in two groups (asymptomatic vs HAM/TSP cases), and observed that persons with SNP rs8099917 genotype GG and rs12979860 genotype CT may present a distinct immune response against HTLV-1 infection. Thus, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for HAM/TSP development.
PMCID: PMC4169378  PMID: 25233462
15.  HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP 
Virology Journal  2014;11:172.
HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation.
We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified ‘strong’ HBZ binders; the remainder were classified ‘weak binders’.
The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders.
Clonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic.
Electronic supplementary material
The online version of this article (doi:10.1186/1743-422X-11-172) contains supplementary material, which is available to authorized users.
PMCID: PMC4192323  PMID: 25270762
HTLV-1; Human T cell lymphotropic virus-type 1; HBZ; HTLV-1 basic leucine zipper factor; HAM/TSP; HTLV-1-associated myelopathy/tropical spastic paraparesis; Integration site; CD8+ T cell
16.  Anti-HTLV antibody profiling reveals an antibody signature for HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) 
Retrovirology  2008;5:96.
HTLV-I is the causal agent of adult T cell leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Biomarkers are needed to diagnose and/or predict patients who are at risk for HAM/TSP or ATLL. Therefore, we investigated using luciferase immunoprecipitation technology (LIPS) antibody responses to seven HTLV-I proteins in non-infected controls, asymptomatic HTLV-I-carriers, ATLL and HAM/TSP sera samples. Antibody profiles were correlated with viral load and examined in longitudinal samples.
Anti-GAG antibody titers detected by LIPS differentiated HTLV-infected subjects from uninfected controls with 100% sensitivity and 100% specificity, but did not differ between HTLV-I infected subgroups. However, anti-Env antibody titers were over 4-fold higher in HAM/TSP compared to both asymptomatic HTLV-I (P < 0.0001) and ATLL patients (P < 0.0005). Anti-Env antibody titers above 100,000 LU had 75% positive predictive value and 79% negative predictive value for identifying the HAM/TSP sub-type. Anti-Tax antibody titers were also higher (P < 0.0005) in the HAM/TSP compared to the asymptomatic HTLV-I carriers. Proviral load correlated with anti-Env antibodies in asymptomatic carriers (R = 0.76), but not in HAM/TSP.
These studies indicate that anti-HTLV-I antibody responses detected by LIPS are useful for diagnosis and suggest that elevated anti-Env antibodies are a common feature found in HAM/TSP patients.
PMCID: PMC2580768  PMID: 18937847
17.  Leukotrienes Are Upregulated and Associated with Human T-Lymphotropic Virus Type 1 (HTLV-1)-Associated Neuroinflammatory Disease 
PLoS ONE  2012;7(12):e51873.
Leukotrienes (LTs) are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1) infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Bioactive LTB4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB4 and LTC4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4+ and CD8+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.
PMCID: PMC3527467  PMID: 23284797
18.  Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I. 
About 1% of people infected with the human T-cell leukaemia virus, type 1 (HTLV-I) develop a disabling chronic inflammatory disease of the central nervous system known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have a vigorous immune response to HTLV-I, and it has been widely suggested that this immune response, particularly the HTLV-I-specific cytotoxic T-lymphocyte (CTL) response, causes the tissue damage that is seen in HAM/TSP. In this paper we summarize recent evidence that a strong CTL response to HTLV-I does in fact protect against HAM/TSP by reducing the proviral load of HTLV-I. We conclude that HTLV-I is persistently replicating at a high level, despite the relative constancy of its genome sequence. These results imply that antiretroviral drugs could reduce the risk of HAM/TSP by reducing the viral load, and that an effective anti-HTLV-I vaccine should elicit a strong CTL response to the virus. The dynamic nature of the infection also has implications for the epidemiology and the evolution of HTLV-I.
PMCID: PMC1692558  PMID: 10365395
19.  Brain Magnetic Resonance Imaging White Matter Lesions Are Frequent in HTLV-I Carriers and Do Not Discriminate from HAM/TSP 
AIDS research and human retroviruses  2007;23(12):1499-1504.
Human T lymphotropic virus (HTLV)-I is known to cause HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other pronounced disease in less than 4% of those infected. However, evidence is accumulating that a proportion of HTLV-I carriers have neurological and urological symptoms without fulfilling criteria for HAM/TSP. Brain white matter (WM) lesions on magnetic resonance imaging (MRI) are frequently seen in HAM/TSP. HTLV-I carriers with MRI scans for other neurological diagnoses have WM lesions more frequently than expected. We studied 10 patients with HAM/TSP and 20 HTLV-I carriers without overt neurological disease and evaluated clinical characteristics, viral load, total, small, large, confluent WM lesion number, and lesion volume on MRI. Cerebral WM lesions were found in of 85% of HTLV-I carriers and 80% of HAM/TSP patients. Lesion number, size or location was no different between carriers and HAM/TSP. Cognitive function was lower in HAM/TSP (p = 0.045) but did not correlate with WM lesion number. Viral load and peripheral blood mononuclear cell interferon-γ production correlated positively (p = 0.001) but did not correlate with lesion number or volume. Conventional brain MRI frequently shows WM lesions in HTLV-I-infected individuals suggesting potential early central nervous system inflammation with rare development of progressive disease.
PMCID: PMC2593463  PMID: 18160007
20.  Immunological and Viral Features in Patients with Overactive Bladder Associated with Human T-Cell Lymphotropic Virus Type 1 Infection 
Journal of medical virology  2012;84(11):1809-1817.
The majority of patients infected with human T-cell lymphotropic virus-type 1 (HTLV-1) are considered carriers, but a high frequency of urinary symptoms of overactive bladder, common in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) have been documented in these patients. The aim of this study was to determine if immunological and viral factors that are seen in HAM/TSP are also observed in these patients. Participants were classified as HTLV-1 carriers (n=45), HTLV-1 patients suffering from overactive bladder (n=45) and HAM/TSP (n=45). Cells from HTLV-1 overactive bladder patients produced spontaneously more proinflammatory cytokines than carriers. TNF-α and IL-17 levels were similar in HAM/TSP and HTLV-1 overactive bladder patients. High proviral load was found in patients with overactive bladder and HAM/TSP and correlated with proinflammatory cytokines. In contrast with findings in patients with HAM/TSP, serum levels of Th1 chemokines were similar in HTLV-1 overactive bladder and carriers. Exogenous addition of regulatory cytokines decreased spontaneous IFN-γ production in cell cultures from HTLV-1 overactive bladder patients. The results show that HTLV-1 overactive bladder and HAM/TSP patients have in common some immunological features as well as similar proviral load profile. The data show that HTLV-1 overactive bladder patients are still able to down regulate their inflammatory immune response. In addition, these patients express levels of chemokines similar to carriers, which may explain why they have yet to develop the same degree of spinal cord damage as seen in patients with HAM/TSP. These patients present symptoms of overactive bladder, which may be an early sign of HAM/TSP.
PMCID: PMC3457650  PMID: 22997085
HTLV-1; immune response; cytokines; chemokines; proviral load
21.  Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy 
PLoS Pathogens  2012;8(1):e1002480.
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.
Author Summary
Infection with the Human T Lymphotropic virus is widespread in the tropics and subtropics, where it causes a chronic disabling disease of the nervous system abbreviated as HAM/TSP. There is no effective treatment available for HAM/TSP, because it is not understood how the virus causes the neuronal damage that results in the clinical symptoms of weakness and paralysis of the legs. Here, we compared the frequencies of cell populations and gene expression profiles from diseased and asymptomatic HTLV-1 carriers to identify abnormalities in biological pathways that cause HAM/TSP. We discovered a distinct group of genes that is over-expressed in white blood cells in patients with HAM/TSP, but not asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The expression of these genes is induced by interferons, a group of anti-viral proteins that are usually beneficial to the host but can also cause inflammation. We also found that interferons did not efficiently suppress HTLV-1 protein expression in vitro. We conclude that interferons do not control chronic HTLV-1 infection but instead contribute to the development of HAM/TSP. Our study provides new insights into the development of HTLV-1-associated diseases and opens new areas of therapeutic intervention.
PMCID: PMC3266939  PMID: 22291590
22.  In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) 
Retrovirology  2009;6:19.
Recently, human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL) development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases.
We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs) and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV-1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1-infected cell was decreased after successful immunomodulatory treatment for HAM/TSP.
These findings suggest that in vivo expression of HBZ plays a role in HAM/TSP pathogenesis.
PMCID: PMC2653460  PMID: 19228429
23.  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.
PMCID: PMC4046198  PMID: 24041428
24.  HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression 
PLoS Pathogens  2013;9(9):e1003630.
Human T-cell leukemia virus type 1 (HTLV-1) causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg) cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4+Foxp3+ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg) cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ). In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4+ T cells were enhanced in these mice. Foxp3−CD4+ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3−T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4+ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.
Author Summary
Viral infection frequently induces tissue inflammation in the host. HTLV-1 infection is associated with chronic inflammation in the CNS, skin, and lung, but the inflammatory mechanism is not fully understood yet. Since HTLV-1 directly infects CD4+ T cells, central player of the host immune regulation, HTLV-1 should modulate the host immune response not only via viral antigen stimulation but also via CD4+ T-cell-mediated immune deregulation. It has been reported that Foxp3+CD4+ T cells are increased in HTLV-1 infection. It remains a central question in HTLV-1 pathogenesis why HTLV-1 induces inflammation despite of increase of FoxP3+ cells, which generally possess immune suppressive function. We have elucidated here that most of the increased Foxp3+ cells in HBZ-Tg mice or HAM/TSP patients is not thymus-derived naturally occurring Treg cells but induced Treg cells. Since the iTreg cells are prone to lose FoxP3 expression and then become cytokine-producing cells, the increase of iTreg cells could serve as a source of proinflammatory CD4+ T cells. Thus HTLV-1 causes abnormal CD4+ T-cell differentiation by expressing HBZ, which should play a crucial role in chronic inflammation related with HTLV-1. This study has provided new insights into the mechanism of chronic inflammation accompanied with viral infection.
PMCID: PMC3777874  PMID: 24068936
25.  CSF CXCL10, CXCL9, and Neopterin as Candidate Prognostic Biomarkers for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis 
Human T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.
Methodology/Principal Findings
Peripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined “deteriorating HAM/TSP” as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and “stable HAM/TSP” as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.
As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.
Author Summary
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease caused by infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 infects 10–20 million people worldwide, and, depending on the region, 0.25–3.8% of infected individuals develop HAM/TSP. As the disease progresses, chronic inflammation damages the spinal cord and lower limb and bladder function gradually decline. In the worst cases, even middle-aged patients can become perpetually bedridden. Today, there are treatments that may alleviate the symptoms to a certain degree, but there is no cure that can halt disease progression, and there are no known biomarkers to indicate the level and speed of disease progression. In this study, we successfully identified three promising candidate biomarkers. We believe that the use of these biomarkers could lead to more accurate prognoses and more prudent, patient-specific treatment plans. We not only hope that these biomarkers are sensitive enough to use as selection criteria for clinical trials, but also that measurements of these biomarkers can be used to accurately evaluate drug effectiveness. In short, the biomarkers we identified have the potential to help more effectively treat current HAM/TSP patients and to pave the way for new drugs to potentially cure future HAM/TSP patients.
PMCID: PMC3794911  PMID: 24130912

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