Human Lymphotrophic Virus Type Research Articles

Regulation of Expression and Latency in BLV and HTLV.

Human T-lymphotrophic virus type 1 (HTLV-1) and Bovine leukemia virus (BLV) belong to the Deltaretrovirus genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 5′ long terminal repeats (5′-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the cis-elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against Deltaretroviruses.

Serosurvey of Human T-Lymphotrophic Virus Type 1 Secondary Infection among People Living with Hiv/Aids in Dutse Metropolis, North-Western Nigeria

Human T-lymphotrophic virus type 1 (HTLV-1) is a causative agent of tropic spastic paraparesis and adult T-cell leukaemia, Evidence is accumulating that HTLV-1 may be responsible for some degree of subclinical immune suppression that may results in increased rate of HIV. Sixty (60) people living with HIV/AIDS consisting of 20 males and 40 females were recruited in this study. HIV diagnosis was confirmed using Nigerian National Serial Algorithm for HIV test. ELISA technique was used for the detection of HTLV-1 IgG and IgM antibodies, and Cyflow partec was used for CD4 count. The prevalence of HTLV-1 IgG and IgM antibodies among HIV subjects was 15% and 6.6% respectively. Male patients have a percentage prevalence of 4(6.6%) and female 5(8.3%) of IgG antibodies, IgM antibodies prevalence was 2(3.3%) for male and female each respectively. CD4 Counts of the HIV subjects was evaluated which reveals that patients with counts 0-200cells/µl tested negative to HTLV-1 IgG and IgM antibodies. Conclusion: The percentage prevalence recorded in this study shows that HTLV-1 infection is relatively high compared to the previous studies even though limited information was obtained in relation to HIV/HTLV-1 co-infection in these study area.

Prevalence studies of human T-Lymphotrophic virus type 1 among pulmonary tuberculosis patients in Dutse metropolis, north-western Nigeria

Human T-lymphotrophic virus type 1 (HTLV-1) is a causative agent of tropic spastic paraparesis and adult Tcell leukaemia, Information regarding the involvement of HTLV-1 in presentation of some subclinical immune suppression that may results in increased rate of HIV and TB infections has long been documented. Sixty (60) Confirmed Pulmonary TB subjects consisting of 41 males and 19 females were recruited in this study, Tuberculosis was confirmed by collecting their sputum samples and analysed using GeneXpert. The prevalence of HTLV-1 IgG antibodies among TB subjects was 6.6%, while that of IgM was 1.6%. Accordingly, sexually active couple group has the highest prevalence of 2.3% when compared to single and widow categories, age group 15-24 has the highest percentage of 3.3% for HTLV-1 IgG antibodies. Key words : HTLV-1, Tuberculosis, IgG, IgM.

Capacidade funcional em indivíduos com paraparesia espástica tropical/mielopatia associada ao HTLV-1

Este estudo teve como objetivo avaliar a capacidade funcional de indivíduos com paraparesia espástica tropical/mielopatia associada ao vírus linfotrófico humano de células T do Tipo 1 (PET/MAH). A pesquisa incluiu 12 indivíduos diagnosticados com HTLV-1 de ambos os sexos, em acompanhamento no Laboratório de Estudos em Reabilitação Funcional (LAERF) da Universidade Federal do Pará (UFPA), através da aplicação do Health Assessment Questionnaire (HAQ). Este é um estudo quantitativo realizado em 2016. Dos participantes 58,3% eram do sexo feminino e 41,6% do sexo masculino. Apresentaram incapacidade moderada à grave 50% dos pesquisados, devido à dificuldade de deambular e alterações na postura e equilíbrio, necessitando assim de auxílio de terceiros e muletas e cadeiras de rodas. A problemática do viver com o HTLV-1 é abrangente e complexa, interferindo no cotidiano, estando relacionada a sintomatologia da doença e requerendo cuidados paliativos na capacidade funcional do dia-a-dia, principalmente, na funcionalidade que envolve os membros inferiores, as transferências de posturas e o equilíbrio.

Cytopathologic Herpes Simplex Virus Features In Laryngeal Squamous Cell Carcinoma

Cytopathologic Herpes Simplex Virus Features In Laryngeal Squamous Cell Carcinoma

High Rates of HTLV-1 Seropositivity in Patients with EBV-Positive Diffuse Large B-Cell Lymphoma

Background: Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) of the elderly is a novel entity included in the most recent edition of WHO Classification of hematologic neoplasms. It usually affects patients older than 60 years of age and carries a poor survival. Human T-lymphotrophic virus type 1 (HTLV-1) is a retrovirus that induces immunosuppression, has been associated with the development of adult T-cell leukemia/lymphoma, and has a high prevalence in Peruvian population.Aim: The goal of this retrospective study was to evaluate the HTLV-1 serological status in EBV-positive DLBCL Peruvian patients.Methods: We identified untreated patients with a diagnosis of DLBCL between January 2002 and June 2015 from the medical records of our institution. IRB approval was obtained prior to data collection. HTLV-1 positivity was defined based on Western Blot analysis. EBV-positivity was defined by identifying at least 10% EBV-encoded RNA (EBER) expression by chromogenic in situ hybridization in the pathological sample. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the immunohistochemical expression of CD20, PAX5, BCL6, CD10, CD30 and MUM-1/IRF4 for re-classification purposes.Results: A total of 210 patients with DLBCL were identified. Of these, 11 patients (5%) were HTLV-1 seropositive and 199 (95%) were HTLV-1 seronegative. Thirty-two patients (15%) were EBV-positive by expression of EBER and 178 (85%) were EBV-negative. HTLV-1 positivity was found in 4/32 (12.5%) of EBV-positive DLBCL patients, and in 7/178 (4%). The odds ratio for HTLV-1 positivity in EBV-positive DLBCL was 3.5 (95% CI 0.7-14.7; p=0.045) when compared with the EBV-negative group. The median age of the HTLV-1-positive DLBCL patients was 65 years (range 45-85 years). There were 5 (45%) men and 6 women (55%). ECOG was >1 in 5 patients (45%), LDH was elevated in 8 (73%), extranodal disease in 7 (64%), and advanced clinical stage (III and IV) in 7 (64%). High IPI score (3-5 factors present) was seen in 8 patients (73%). Interestingly, all the patients who were EBV-positive and HTLV-1-positive presented with early stage (I and II), normal LDH levels and low IPI scores (0-2 factors).Conclusions: There is a high prevalence of HTLV-1 seropositive status in patients with EBV-positive DLBCL. Patients with double EBV and HTLV-1 positivity appear to present at earlier stages and with lower risk disease. Larger studies are needed to confirm these findings. DisclosuresNo relevant conflicts of interest to declare.

A new ATL xenograft model and evaluation of pyrrolidine dithiocarbamate as a potential ATL therapeutic agent

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-lymphotrophic virus type 1 infection and is one of the most refractory malignant T-cell lymphomas. Improvement of ATL therapy options requires the establishment of appropriate ATL animal models. In this study, we successfully generated an ATL mouse model by xenotransplantation of primary peripheral blood mononuclear cells (PBMCs) isolated from ATL patients (ATL cells) into nonobese diabetic/severe combined immunodeficiency/Jak3-null mice (NOJ mice). To generate the model, the ATL S1T cell line was subcutaneously injected into mice. Primary ATL cells were then transplanted subcutaneously, intraperitoneally, or intravenously. ATL cells infiltrated multiple organs, and elevated human soluble interleukin 2 receptor (IL-2R) levels were detected in peripheral blood. Injection of one million primary ATL cells was needed for successful engraftment into host mice. Thawed cells, frozen long-term in liquid nitrogen, could also be transplanted; however, more cells were required to achieve similar results. The median mouse survival time was proportional to the number of cells injected. Successful secondary transplantation of ATL cells from one NOJ mouse into another was achieved and confirmed by T-cell receptor analysis. Finally, we examined the effects of the antioxide pyrrolidine dithiocarbamate (PDTC) as an antitumor agent in vivo. PDTC administration inhibited the increase of soluble IL-2R and improved mouse survival, suggesting that this compound has potential as an anti-ATL agent. We demonstrated that ATL cells could be stably xenotransplanted into NOJ mice using primary cells. This model will be useful in the establishment of novel therapies to treat ATL.

A multisystem diagnostic mystery: unilateral weakness, a rash, and lymphadenopathy.

A multisystem diagnostic mystery: unilateral weakness, a rash, and lymphadenopathy.

Atrophy, focal spinal cord lesions and alterations of diffusion tensor imaging (DTI) parameters in asymptomatic virus carriers and patients suffering from human T-lymphotrophic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

In tropical spastic paraparesis, spinal cord atrophy is a well-known finding in magnetic resonance imaging. But in contrast to histological reports, focal lesions of the spinal cord have only been described in imaging reports in exceptional acute cases. Here, we looked for such focal lesions and for alterations of diffusion tensor imaging parameters of the long fibre tracts in the usual case of a long-standing and slowly progressive disease. We examined 10 symptomatic patients, 11 seropositive, but asymptomatic human T-lymphotrophic virus type 1 carriers and 18 seronegative volunteers as controls. Sagittal and transversal T2-weighted images were visually assessed for atrophy and focal cord lesions. The spinal cord cross-sectional areas and the segmental cord volumes were measured at all levels. High-resolution diffusion tensor imaging was performed in sagittal planes from the bregma down to the cervical spine. For tractography and calculation of fractional anisotropy and mean diffusivity, we used manufacturer-provided software. Two-thirds of patients showed focal lesions affecting the antero-lateral columns and in two cases also the dorsal columns. Compared to carriers and volunteers, patients presented a significant spinal cord atrophy and a reduction of fractional anisotropy (p < 0.05), correlating more to duration of symptoms than to clinical impairment. Because our carriers did not show a significant atrophy, focal lesions or a change of diffusion tensor imaging parameters, we need further long-term studies to see if these parameters at some stage may be used as early indicators of spinal cord affection in virus carriers.

Rapid quantitative detection of Human immunodeficiency virus type 1 by a reverse transcription-loop-mediated isothermal amplification assay

Accurate and rapid quantitation of Human immunodeficiency virus type 1 (HIV-1) RNA levels is a critical aspect in estimating the effect of antiviral therapy and establishing therapeutic schedule. Thus, for the first time, a rapid quantitative reverse transcription-loop-mediated isothermal amplification (RT-LAMP) was designed to quantitate HIV-1 RNA. The results showed that the dynamic range was from 2.5×10(2) to 10(7) copies with a coefficient of determination (R(2)) of 0.991, and the limit of detection of RT-LAMP by Probit analysis at the 95% detection level was 196 copies. The intra-assay coefficient of variation (CV) ranged from 0.67% to 2.08% at 10(7) copies and 7.25% to 12.97% at 250 copies. The CVs of inter-assay were 2.39% and 13.93% for the high and low copy numbers, respectively. No cross-reaction with Human immunodeficiency virus type 2 (HIV-2), Human T lymphotrophic virus type 1 (HTLV-1) and Hepatitis C virus (HCV) was observed and a good agreement between the RT-LAMP method and the real-time reverse transcription-polymerase chain reaction (qRT-PCR) test was achieved. This proposed RT-LAMP method could be useful for rapid diagnosis of high risk group and pharmacodynamic assessment of anti-HIV drug, especially in less-equipped laboratories of impoverished areas.

Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma is a rare mature CD4(+) T-cell neoplasm caused by the retrovirus human T-lymphotrophic virus type 1. At present there are approximately 20 million people infected globally with this virus, and most of these individuals belong to the endemic areas in southern Japan, Africa, the Caribbean basin, and Latin America. In the United States, it is usually seen in immigrants from these endemic regions. Adult T-cell leukemia/lymphoma predominantly affects the adult population and is rare in children. Adult T-cell leukemia/lymphoma has 4 subtypes: acute, lymphomatous, chronic, and smoldering. Clinically, the first 2 variants are classified as aggressive, and the latter two are classified as indolent. Given the rare occurrence and diagnostic challenges associated with adult T-cell leukemia/lymphoma, this review will highlight its salient features to aid in recognition of this entity and perform a comprehensive diagnostic workup.

Animal models of bovine leukemia virus and human T-lymphotrophic virus type-1: insights in transmission and pathogenesis.

Bovine leukemia virus (BLV) and human T-lymphotrophic virus type-1 (HTLV-1) are related retroviruses associated with persistent and lifelong infections and a low incidence of lymphomas within their hosts. Both viruses can be spread through contact with bodily fluids containing infected cells, most often from mother to offspring through breast milk. Each of these complex retroviruses contains typical gag, pol, and env genes but also unique, nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the pathogenesis of each virus. Comparisons of BLV and HTLV-1 provide insights into mechanisms of spread and tumor formation, as well as potential approaches to therapeutic intervention against the infections.

Triple Infection with HIV-1, Htlv-1 and Strongyloides Stercoralis, Rendering Cd4+ T- C E L L Counts a Misleading Entity

We report the case of a Gabonese HIV-patient who presented with haemoptysis, weight loss, fulminant diarrhoea and subsequent ileus and elevated CD4+ T-cell counts. He was diagnosed with Strongyloides stercoralis and human T-lymphotrophic virus type-1 infection. After treatment of the strongyloides hyperinfection syndrome, his CD4+ T-cell counts dropped greatly. The initially elevated CD4+ T-cell counts were misleading to the clinicians with regard to decision-making on antiretroviral therapy initiation.

Not All Aggressive Adult T-Cell Leukemia/Lymphoma Subtypes Are Created Equal

presentedwhatisprobablythelargeststudytoevaluateprognosticfactorsinpatientswithadult T-cell leukemia/lymphoma (ATLL) to date; the study includedmore than 800 patients. The proposed prognostic index (PI), calledATL-PI by the authors, consists of five adverse variables: stage III/IV,EasternCooperativeOncologyGroupperformancestatus0-1,age 70years,serumalbuminlevel 3.5g/dL,andsolubleinterleukin-2receptorlevel 20,000U/mL.Accordingtotheriskcategory,patientswithhigh-,intermediate-,andlow-riskdiseaseexperiencedamedianoverallsurvivaltimeof4.6,7,and16.2months,respectively.ATLL is a rare type of peripheral T-cell lymphoma (PTCL) thatdevelops in individuals with a chronic infection by the humanT-lymphotrophic virus type I. The epidemiology of ATLL, not surpris-ingly, mimics that of human T-lymphotrophic virus type I and affectsindividualslivinginspecificgeographicregionssuchasJapan,theCarib-bean,CentralandSouthAmerica,NorthernAfrica,andtheMiddleEast.Clinically,ATLLhasatleastfourvariants:acute(leukemic),lymphoma-tous,smoldering,andchronic.Classically,theacuteandlymphomatoussubtypeshavebeenassociatedwithaworseprognosis.However, there are specific distinctions between the acute andlymphomatous subtypes of ATLL. First, few studies have shown ge-netic and pathophysiologic heterogeneity within the aggressive vari-ants of ATLL. Oshiro et al

Development of Tropical Spastic Paraparesis in Human T-Lymphotropic Virus Type 1 Carriers Is Influenced by Interleukin 28B Gene Polymorphisms

Interleukin 28B (IL28B) rs12979860 polymorphisms were examined in 41 individuals with human T-lymphotrophic virus type 1 (HTLV-1). The alleles CT/TT were more frequent in 12 individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis than in 29 asymptomatic carriers (80% vs 20%; P = .03), and median HTLV-1 proviral load was greater in CT/TT than CC carriers (P = .01). Thus, IL28B testing and closer follow-up of HTLV-1 asymptomatic CT/TT carriers is warranted.

Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.

Neuroimmunity of HTLV-I Infection

Human T-lymphotrophic virus type I (HTLV-I) is an oncogenic retrovirus and its infection is associated with a variety of human diseases including HTLV-I-associated myelopathy/tropic spastic paraparesis (HAM/TSP). Large numbers of epidemiological, virological, immunological, and clinical studies on HTLV-I- and HTLV-I-associated diseases have been published, although the pathogenesis of HAM/TSP remains to be fully understood. In the last several years, researchers have shown that several key factors are important in HTLV-I-associated neurologic disease including high HTLV-I proviral load and a strong immune response to HTLV-I. Here, we review pathophysiological findings on HAM/TSP and focus on viral-host immune responses to the virus in HTLV-I infected individuals. In particular, the role of HTLV-I-specific CD8+ T cell response is highlighted.

Abstract 4524: Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of a novel Bcl-2 family inhibitor, ABT-737

Abstract Adult T-cell lymphoma/leukemia (ATLL) is a T-cell malignancy caused by the human T-lymphotrophic virus type I (HTLV-I), and its therapeutic outcome still remains extremely poor. Therefore, novel therapeutic strategies are needed to improve treatment outcomes. In this study, we elucidated the therapeutic potential of targeting the anti-apoptotic Bcl-2 family proteins for the treatment of ATLL using ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. We first validated the rationale of this study by immunohistochemically assessing the expression of Bcl-2 family proteins in 25 lymph-node specimens derived from ATLL patients. The Bcl-2 and/or Bcl-XL proteins were expressed in 80% of specimens. We next examined the cytotoxicity of ABT-737 against three ATLL cell lines by the Colorimetric method. ABT-737 significantly inhibited growth of MT-1, MT-2 and HuT 102 cells with concentrations of 50 percent inhibition of 2.4, 0.23 and 0.008μM at 72 h, respectively. We then tried to clarify the mechanism of growth inhibition induced with ABT-737 using MT-1 and MT-2 cells. ABT-737 induced apoptosis in both cells with cleavage of caspases 9 and 3, and PARP. ABT-737 also induced apoptosis in fresh tumor cells derived from patients with ATLL. We also tested if ABT-737 enhances the cytotoxicity induced by conventional chemotherapeutic agents or novel agents. The interactions between them were evaluated using the Chou-Talalay method. ABT-737 synergistically enhanced the cytotoxicity and apoptosis induced by doxorubicin, vincristine or etoposide and bortezomib or suberolyanilide hydroxamic acid, which are current key drugs and promising candidates for the treatment of ATLL, respectively. Finally, we investigated the growth inhibition of ABT-737 in ATLL-xenografted mice. The mean tumor volume and weight, and mean serum level of soluble interleukin-2 receptor α at day 21 of the treated mice with ABT-737 (100mg/kg/day) were significantly lower than those of vehicle-treated mice. Moreover, massive induction of apoptosis was observed in tumors treated with ABT-737 by the TUNEL assay. These results suggest that the use of ABT-737, either alone, or in combination with other conventional cytotoxic and novel drugs, represents a promising novel targeted approach to overcome drug resistance and to improve patient outcome in ATLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4524.

Targeting Bcl-2 Family Proteins in Adult T-Cell Leukemia/Lymphoma: In Vitro and In Vivo Effects of a Novel Bcl-2 Family Inhibitor ABT-737.

Abstract 1685Poster Board I-711Adult T-cell lymphoma/leukemia (ATLL) is a T-cell malignancy caused by human T-lymphotrophic virus type I (HTLV-I), and its therapeutic outcome is still remains very poor. Therefore, novel therapeutic strategies are needed to improve patient outcome. In this study, we elucidated the therapeutic potential to target anti-apoptotic Bcl-2 family proteins for the treatment of ATLL by using ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. We first validated the rationale of this study by assessing the expression of Bcl-2 family proteins among 25 lymph-node specimens derived from ATLL patients by using immunohistochemistory. Both or either of Bcl-2 and Bcl-XL proteins was highly expressed in 80% of specimens. We next examined the cytotoxicity of ABT-737 against ATLL cell lines. ABT-737 significantly inhibited growth of MT-1, MT-2 and HuT 102 cells with a concentration of 50 percent inhibition (IC50) at 72 h of 2.4, 0.23 and 0.008μM, respectively. We then elucidated the mechanism of growth inhibition induced by ABT-737 using MT-1 and MT-2 cells. ABT-737 induced apoptosis in MT-1, MT-2 cells with cleavage of caspase 9, 3 and PARP. ABT-737 also induced apoptosis in fresh tumor cells derived from patients with ATLL. We next elucidated the potential of ABT-737 to enhance the cytotoxicity induced by conventional chemotherapeutic agents. The interaction between them was evaluated using the Chou-Talalay method by determining the combination index. ABT-737 synergistically enhanced the cytotoxicity and apoptosis induced by either of doxorubicin, vincristine or etoposide, which is a current key drug to treat ATLL. Most importantly, ABT-737 significantly inhibited tumor growth of in vivo ATLL model using SCID mice inoculated by HuT 102 cells subcutaneously. The mean tumor volume, weight and serum level of soluble interleukin-2 receptor á of ABT-737 (100mg/kg/day)-treated mice were significantly lower than those of vehicle-treated mice after treatment for 21 days. Moreover, massive induction of apoptosis in tumors treated by ABT-737 was observed by immunofluorescent TUNEL assay. These results suggest that ABT-737 used either alone or in combination with conventional cytotoxic drugs, represents a promising novel targeted approach to overcome drug resistance and improve patient outcome in ATLL. DisclosuresNo relevant conflicts of interest to declare.

Immunological Function against Human T-Lymphotrophic Virus Type I in Carriers with Collagen Diseases and HAM/TSP.

Human T-cell leukemia virus-1 (HTLV-1) is the first human retrovirus that has infected approximately 10–20 million people worldwide and causes adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) after long-term chronic infection. The immune response to HTLV-1 is typically enhanced in HAM/TSP, while impaired cell-mediated immunity has been identified as a causative basis of immunodeficiency in ATLL. The negative immuno-regulatory program death-1 (PD-1) signaling is involved in auto-immunity, allergy, sites of immune privilege, and antitumor immunity. We have previously reported decreased frequency and function of HTLV-1 Tax-specific CD8+ T-cell in ATLL patients due to insufficient cytolytic effector molecules, as well as upregulated PD-1 expression on HTLV-1-specific CTLs from asymptomatic carriers (ACs) and ATLL patients. That PD-1 expression was significantly higher on HTLV-1 specific CD8+ T-cells, as well as CMV− and EBV-specific CTLs in ATLL patients compared to ACs, suggested that PD-1 signaling plays a role in fostering persistent HTLV-1 infections, facilitating immune evasion by ATLL cells, which may further ATLL development (ASH annual meeting 2006, 2007). However, there is no report on the repertoir and PD-1 expression of HTLV-1-specific CTL in carriers with hyper immune states such as collagen disease or HAM/TSP. Therefore, to characterize HTLV-1-specific CTL in asymptomatic HTLV-1 carriers (ACs), carriers with collagen disease (CCs) and HAM/TSP patients, we examined the frequency, diversity and PD-1 expression of HTLV-1-specific CTL in 23 ACs, 33 carrier with collagen vascular disease, 40 HAM/TSP patients and 18 healthy donors (HDs) using 16 distinct HTLV-1 Tax/Env HLA-A*0201 and HLA-A*2402 tetramers. The difference in frequency of HTLV-1 Tax-specific CTL positivity was not statistically significant between CCs, HAM/TSP or ACs. In contrast, HTLV-1 Env-specific CTL were significantly more frequent in autoimmune disorders and HAM/TSP than those in ACs (Table 1). On the other hand, percentages of CD8+ lymphocytes from these carriers expressing PD-1 were significantly higher than that from HDs. Futhermore, the rates of PD-1 expression on CMV- or EBV-specific CTL in CCs, HAM/TSP and ACs were similar although PD-1 expression was significantly down-regulated on HTLV-1-specific CTL in CCs and HAM/TSP compaired to ACs (Figure1, p<0.05 and p<0.01, respectively). Few lymphocytes from these carriers were positive for the PD-L1 ligand, while PD-L1 expression was observed on lymphocytes cultured for 12 hours from ACs (5 of 6), but less from CCs and HAM/TSP (1 of 6 and 0 of 4, respectively). The diversity, frequency and repertoir of HTLV-1-specific CD8+ T cell clones, especially HTLV-1 Env CTLs, may be related to the hyper immune response in CCs and HAM/TSP. The down-regulation of PD-1 on HTLV-1 Tax-specific CTL and loss of PD-L1 expression in CCs and HAM/TSP may explain the apparent hyper immune response against HTLV-1 Tax protein.Table 1. HTLV-1/HLA tetramers positive subjectsHLA alleleTetramersACCCHAM/TSPA*02Tax100% (8/8)75% (9/12)90% (9/10)A*02Env0% (0/8)25% (3/12)10% (1/10)A*24Tax94% (17/18)88% (21/24)100% (15/15)A*24Env6% (1/18)63% (15/24)*40% (6/15)*Tax CTL96% (22/23)82% (27/33)100% (18/18)Eav CTL4% (1/23)48% (16/33)*50% (9/18)*The number of subjects positive for tetramers; the percentages of HTLV-1/HLA tetramer+ CD8+ T cells in the CD8+ lymphocytes > 0.1% are counted as subjects positives for tetramer, *, P < 0.01, significant differences from AC by χ2 test. [Display omitted]