Human T-lymphotropic Virus Type I Carriers Research Articles

Interactions between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases among the Japanese population.

BackgroundAn increased risk of total death owing to human T-lymphotropic virus type-I (HTLV-I) infection has been reported. However, its etiology and protective factors are unclear. Various studies reported fluctuations in immune-inflammatory status among HTLV-I carriers. We conducted a matched cohort study among the general population in an HTLV-I-endemic region of Japan to investigate the interaction between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases.MethodWe selected 2180 sub-cohort subjects aged 35–69 years from the cohort population, after matching for age, sex, and region with HTLV-I seropositives. They were followed up for a maximum of 10 years. Inflammatory gene polymorphisms were selected from TNF-α, IL-10, and NF-κB1. A Cox proportional hazard model was used to estimate the hazard ratio (HR) and the interaction between gene polymorphisms and HTLV-I for risk of total death and incidence of cancer and atherosclerosis-related diseases.ResultsHTLV-I seropositivity rate was 6.4% in the cohort population. The interaction between TNF-α 1031T/C and HTLV-I for atherosclerosis-related disease incidence was statistically significant (p = 0.020). No significant interaction was observed between IL-10 819T/C or NF-κB1 94ATTG ins/del and HTLV-I. An increased HR for total death was observed in the Amami island region, after adjustment of various factors with gene polymorphisms (HR 3.03; 95% confidence interval, 1.18–7.77).ConclusionThe present study found the interaction between TNF-α 1031T/C and HTLV-I to be a risk factor for atherosclerosis-related disease. Further follow-up is warranted to investigate protective factors against developing diseases among susceptible HTLV-I carriers.

Human T-Lymphotropic Virus Type I-Associated Myelopathy

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is a chronic progressive myelopathy that is characterized by spastic paraparesis with bladder dysfunction that is derived from bilateral pyramidal tract involvement and neurogenic bladder, respectively. The primary neuropathological feature of HAM is chronic inflammation in the spinal cord, mainly the lower thoracic cord, which is characterized by perivascular cuffing and parenchymal infiltration of mononuclear cells. Although it is still unclear why only a very small proportion of HTLV-I carriers develop HAM, the key player in the pathogenesis of HAM is the increase of activated HTLV-I-infected cells in the peripheral blood. The exact cellular and molecular events underlying the induction of chronic inflammation in the spinal cord by HTLV-I are still unclear. However, a long-standing bystander mechanism, such as the destruction of surrounding nervous tissue by the interaction between HTLV-I-infected CD4+ T cells and HTLV-I-specific cytotoxic T cells in the spinal cord, with the cooperation of the positive feedback loop of inflammation that is derived from the migrated HTLV-I-infected cells is probably critical in the immunopathogenesis of HAM. In this review, recent advances in several fields toward the elucidation of the pathomechanisms concomitant with the establishment of new therapeutic strategies in HAM will be discussed along with an overview of the clinical features.

Intracellular cyclic adenosine monophosphate regulates the efficiency of intercellular transmission of human T-lymphotropic virus type I

Objective To investigate the relationship between the intercellular transmission efficiency of human T-lymphotropic virus type I (HTLV-I) and the signaling involved in actin polymerization during cytoskeletal reorganization in a comparative study of HTLV-I-infected T-cell lines derived from an HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient or an HTLV-I carrier. Methods HCT-5 and TL-Su cells derived from an HAM/TSP patient and an HTLV-I carrier, respectively, were used as HTLV-I-infected T-cell lines. After co-cultivation of each HTLV-I-infected T-cell line with H9/K30 luc reporter cells, the relative luc activities were calculated to analyze the efficiency of intercellular transmission of HTLV-I. The intracellular levels of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) were measured in enzyme-linked immunoassays. The expression of phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) was analyzed by western blotting. Results Treatment of HCT-5 cells with latrunculin B, an inhibitor of actin polymerization, significantly suppressed the relative luc activity. Western blotting analysis of HCT-5 cells treated with the adenylyl cyclase activator forskolin showed upregulation of p-VASP, with a concomitant and significant increase in the intracellular cAMP concentration. Furthermore, the relative luc activity was significantly decreased. The intracellular cAMP, but not cGMP levels, were significantly lower in HCT-5 than in TL-Su. Vasodilator-stimulated phosphoprotein appeared less phosphorylated in HCT-5 than in TL-Su. The relative luc activity was significantly higher in HCT-5 than in TL-Su. Conclusions The intracellular cAMP concentration regulates the efficiency of intercellular HTLV-I transmission under the control of p-VASP expression, suggesting the intercellular transmission potential of HTLV-I-infected T cells of HAM/TSP patients is enhanced by downregulated intracellular cAMP levels.

The Impact of Immune Response on HTLV-I in HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

Human T lymphotropic virus type I (HTLV-I) is a retrovirus which is associated with adult T cells leukaemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of HTLV-I-infected individuals. It is not clear why a minority of HTLV-I-infected individuals develop HAM/TSP and majority remains lifelong carriers. It seems that the interaction between the virus and the immune response plays an important role in HTLV-I-associated diseases. Although the role of the immune response in HTLV-I pathogenesis is not fully understood, however it seems that the efficacy of the immune response which is involved in controlling or limiting of viral persistence determines the outcome of HTLV-I-associated diseases. Here we discuss the role of innate and adaptive immune response and also the risk factors contribute to the observed differences between HAM/TSP patients and asymptomatic HTLV-I carriers.

Human T‐lymphotropic virus type I (HTLV‐I)‐specific CD8+ cells accumulate in the lungs of patients infected with HTLV‐I with pulmonary involvement

Pulmonary involvement has been identified in human T-lymphotropic virus type I (HTLV-I) carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the relationship between HTLV-I infection and lung disease is poorly understood. The occurrence of HTLV-I-specific immune responses in the lungs of patients infected with HTLV-I with pulmonary involvement was investigated. The frequency of HTLV-I-specific CD8+ cells and the amount of HTLV-I proviral DNA were determined in bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells (PBMCs) from five patients with HAM/TSP and one HTLV-I carrier who had pulmonary involvement. HTLV-I-specific CD8+ cells were detected by flow cytometry using human leukocyte antigen/antigen complex multimers. The analysis of bronchoalveolar lavage fluid revealed lymphocytosis in five of six patients. HTLV-I provirus was detected in the bronchoalveolar lavage fluid cells of all patients, and the proviral load in these cells was comparable to that in PBMCs. The frequency of HTLV-I-specific CD8+ cells in the bronchoalveolar lavage fluid cells was 5.1 times higher than that in PBMCs. Immunohistochemically, clusters formed by HTLV-I-specific CD8+ cells were detected in lung tissue by in situ tetramer staining. No samples were available from patients infected with HTLV-I without lung disorders. Whether accumulation of CD8+ cells is specific to patients with pulmonary involvement remains unclear. These results indicate that HTLV-I-specific CD8+ cells accumulate and HTLV-I-infected cells exist in the lungs of patients infected with HTLV-I with pulmonary involvement.

Reduced Tim-3 Expression on Human T-lymphotropic Virus Type I (HTLV-I) Tax-specific Cytotoxic T Lymphocytes in HTLV-I Infection

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) and programmed cell death-1 (PD-1) are T cell exhaustion molecules. We investigated the expression of Tim-3 and PD-1 in human T-lymphotropic virus type I (HTLV-I) infection. Tim-3 expression, but not PD-1 expression, was reduced on CD4(+) and CD8(+) T cells of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-I carriers as compared with healthy controls. Tim-3 expression was also reduced in HTLV-I Tax-specific cytotoxic T lymphocytes (CTLs) as compared with cytomegalovirus-specific CTLs. Tim-3(+), but not PD-1(+), Tax-specific CTLs produced less interferon-γ and exhibited low cytolytic activity. However, we observed no difference in the expression of Tim-3 or cytolytic activity between Tax-specific CTLs of HAM/TSP patients or carriers. Moreover, HTLV-I-infected CD4(+) T cells showed decreased Tim-3 expression. These data suggest that Tim-3 expression is reduced in HTLV-I infection and that a high number of Tim-3(-) HTLV-I-specific CTLs preserves their cytolytic activity, thereby controlling viral replication.

Population differences in immune marker profiles associated with human T‐lymphotropic virus type I infection in Japan and Jamaica

The natural history of human T-lymphotropic virus type I (HTLV-I) has been shown to differ markedly by geographic area. The differences include contrasting patterns of risk of adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may be due in part to differences in host immune response to infection. To characterize variations in host immunity across populations, we compared serologic immune marker patterns in HTLV-I-endemic populations in Japan and Jamaica. We matched 204 participants with archived blood from the Miyazaki Cohort Study (Japan) and the Food Handlers Study (Jamaica)-i.e., 51 HTLV-I-positive ("carriers") and 51 HTLV-I-negative individuals ("noncarriers") from each population-by age, sex and blood collection year. We compared plasma concentrations of markers of T-cell-mediated (antigen-specific) and nonspecific immunity using regression models and correlation coefficients. Compared to Jamaican HTLV-I noncarriers, Japanese noncarriers had higher covariate-adjusted mean levels of T-cell activation markers, including antibody to Epstein-Barr virus nuclear antigen-1 (reciprocal titer 27 vs. 71, respectively, p=0.005), soluble interleukin-2 receptor-alpha (477 vs. 623 pg/mL, p=0.0008) and soluble CD30 (34 vs. 46 U/mL, p=0.0001) and lower levels of C-reactive protein (1.1 vs. 0.43 microg/mL, p=0.0004). HTLV-I infection was associated with activated T-cell immunity in Jamaicans but with diminished T-cell immunity in Japanese persons. The observed population differences in background and HTLV-I-related host immunity correspond closely to the divergent natural histories of infection observed among HTLV-I carriers in Japan and Jamaica and corroborate a role for host immune status in the contrasting patterns of ATL and HAM/TSP risk.

Patterns of serum type 1 and type 2 immune markers in healthy carriers of HTLV‐I

Type 1 immunity appears to be diminished in healthy Japanese carriers of human T-lymphotropic virus type I (HTLV-I), but type 2 status remains undetermined. To further examine the subclinical effect of HTLV-I on host immunity, we measured serum antibodies to the Epstein-Barr virus (EBV) in 415 healthy Japanese adults to broadly characterize type 1 status. Levels of the type 2 biomarkers total immunoglobulin E (IgE), soluble CD23 (sCD23), and soluble CD30 (sCD30) were assessed in 167, 142, and 135 of these subjects, respectively. We analyzed the association of HTLV-I with levels of each serum marker using linear and logistic regression. Altered EBV antibody profiles that are consistent with deficient type 1 immunity were more prevalent in HTLV-I carriers than non-carriers (odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.5-5.3). Carriers also had 45% lower total IgE levels (P = 0.04) than non-carriers. In contrast, HTLV-I infection was not significantly associated with elevated levels of sCD23 or sCD30. These observations are contrary to our expectation of elevated type 2 biomarkers among carriers. We conclude that in this population, healthy carriers of HTLV-I may have subclinical deficiencies in both type 1 and type 2 immunity, and that type 1 and type 2 immunity are not necessarily reciprocal in persons with subclinical immune dysregulation.

P53 codon 72 polymorphism is associated with disease progression in adult T‐cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATL) is associated with the monoclonal integration of human T-lymphotropic virus type I (HTLV-I) proviral DNA into tumour cells, but the incidence of ATL is low (2–5%) among HTLV-I carriers and those who develop the disease usually have a 40- to 60-year latency period from the time of infection to progression to ATL. These phenomena suggest that additional mechanisms are involved in the progression of the disease, such as inactivation of tumour suppressor genes. P53 is one of the most important tumour suppressor genes that is involved in multiple pathways including apoptosis, cellular transcriptional control and cell cycle regulation. A common polymorphism of P53 at codon 72 results in either a variant protein with a proline (Pro) residue (CCC) or an arginine (Arg) amino acid (CGC) (Zhang et al, 2003). Recent studies have found that this polymorphism is associated with susceptibility or progression of several kinds of cancers (Zhang et al, 2003). However, data are not available as to whether this polymorphism plays a role in the pathogenesis of ATL among HTLV-I carriers. Human T-lymphotropic virus type I carriers (n = 81) were identified in the general population in an endemic region for HTLV-I, the Nagasaki district of Japan, after a mass medical and laboratory screening for individuals with anti-HTLV-I serum antibodies. ATL patients (n = 87) were diagnosed at the Department of Haematology, Nagasaki University School of Medicine. HTLV-I negative controls (n = 89) were included in the analysis. All subjects were Japanese. The genotype was performed as previously described (Zhang et al, 2003). Allele frequency of the P53 codon 72 polymorphism was not statistically different between 89 HTLV-I negative controls and 81 healthy HTLV-I carriers (P = 0·677) (Table I). These data suggest that genetic polymorphism in the P53 locus does not play a role in the infection of the HTLV-I. The allele frequency was not statistically different between 87 individuals with ATL and 81 healthy HTLV-I carriers (P = 0·627). These data suggest that this polymorphism does not play a role in the development of ATL among HTLV-I carriers. We previously found that a genetic polymorphism of the tumour necrosis factor gene enhanced susceptibility to ATL among HTLV-I carriers (Tsukasaki et al, 2001). In contrast, polymorphisms at the methylenetetrahydrofolate reductase locus did not alter susceptibility to ATL (Takeuchi et al, 2004). The frequency of the P53 codon 72 genotype in clinically defined subtypes of ATL is shown in Table I. Of note, the frequency of the arginine homozygous allele was higher in acute ATL than in chronic ATL (P = 0·0396). These results suggest that the P53 polymorphism plays an important role in the progression of ATL. Previous studies showed that mutation of the P53 gene in acute ATL was higher than that in chronic ATL (Hatta & Koeffler, 2002). We have previously reported that the frequency of adenomatous polyposis coli (APC) promoter methylation in acute type ATL (57%) was much higher than in chronic type ATL (13%) (P = 0·03) (Yang et al, 2005). Several differences occur among the P53 variants in their ability to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis and to repress the transformation of primary cells (Thomas et al, 1999). Polymorphism of the P53 gene is associated with increased susceptibility to the development of gastric, urinary tract and breast cancers (Zhang et al, 2003). Taken together, P53 may have functional importance in several types of malignancies including ATL, probably by modulating its efficiency as a transcription factor. This work was supported in part by grants from National Institutes of Health, Honara Shapiro Fund, Parker Hughes Trust, Sherly and David Weisberg Foundation, grant-in-aid from the Ministry of Education, Culture Sports, Science and Technology of Japan. H. P. K. is a member of the Jonsson Comprehensive Cancer Center and Molecular Biology Institute of UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

Progressive multifocal leukoencephalopathy in an HTLV-I carrier

This report describes a previously 28-year-old healthy woman, identified as an asymptomatic human T-lymphotropic virus type I (HTLV-I) carrier, who developed both progressive multifocal leukoencephalopathy (PML) and Pneumocystis jiroveci pneumonia. For diagnostic confirmation of PML, stereotactic brain biopsy demonstrated multiple demyelinating lesions with the presence of JC viral antigen. Intramuscular α-interferon therapy for 2 weeks brought considerable neurologic improvement. Three years later, the patient developed lymphoma-type of adult T-cell leukemia, suggesting that HTLV-I carrier might be one of the underlying diseases of PML.

A carrier of human T-lymphotropic virus type I with periodic limb movements progressing to myelopathy

Human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia and HTLV-I-associated myelopathy (HAM). HAM is characterized by slowly progressive paraplegia but often presents with involuntary movements. Periodic limb movements (PLMs), characterized by stereotyped, repetitive, nonepileptiform movements of the legs, with HAM are usually associated with motor paresis or occur after the development of myelopathy. We describe an HTLV-I carrier presenting with PLMs that progressed to myelopathy (HAM). A 34-year-old woman had a 4-year history of involuntary leg movements during sleep. Restless legs syndrome had been diagnosed at another hospital in August 2002. MRI of the brain, cervical spine, and lumbar spine showed no abnormalities. The EEG was normal. CSF showed 4 white blood cells (WBCs)/mm3 and a protein level of 44 mg/dL. The anti-HTLV-I antibody was positive in CSF (×8). The patient's mother was a healthy HTLV-I carrier. Because involuntary movements developed despite treatment with levodopa and clonazepam, the patient was admitted to our hospital in December 2002. The deep tendon …

Clonally rearranged T‐cell receptor β chain genes in HTLV‐I carriers with abnormal, non‐flower‐like, lymphocytes

The diagnosis of Adult T-cell leukemia/lymphoma ATLL subtypes in human T-lymphotropic virus type I (HTLV-I) carriers based in morphology and immunophenotype of lymphocytes can be challenger. We propose that polymerase chain reaction (PCR) amplification of the rearranged TCR gene in HTLV-I healthy carriers would be a convenient method for establishing the nature of the circulating T lymphocytes in asymptomatic HTLV-I carriers, presenting only mild and inconclusive signals of deviation from normality. Using PCR, we analyzed the genetic recombination pattern of the T-cell beta-chain receptor gene (TCR-beta) in order to identify clonal expansion of peripheral blood T lymphocytes in 17 HTLV-I-positive healthy carriers and in nine normal HTLV-I-negative blood donors. To evaluate the performance of PCR in detection of clonality, we also analyzed 18 patients with post-thymic/mature T-cell malignancies presenting circulating abnormal lymphocytes. Seven of the 17 HTLV-I positive individuals presented circulating abnormal lymphocytes; monoclonal or oligoclonal expansion of T-cells was detected in five of the 17 HTLV-I-positive individuals, all of them presenting abnormal lymphocytes. Clonal expansion was not detected in any of the negative controls or in any of the 12 remaining healthy carriers. All patients in the positive control group tested positive by PCR and Southern blots. Southern blots were negative for all 17 healthy carriers. PCR amplification of segments of rearranged TCR-beta is reliable for allowing early detection of small populations of clonal T cells in blood samples from asymptomatic HTLV-I carriers, providing an additional alert in the follow-up of carriers with abnormal circulating lymphocytes.

Erectile dysfunction and HTLV-I infection: a silent problem

The human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with a chronic myelopathy known as HTLV-I-Associated Myelopathy or Tropical Spastic Paraparesis (HAM/TSP). The main objective was to assess the frequency of erectile dysfunction (ED) in HTLV-I-infected individuals from Salvador and other cities from Bahia, Brazil, as well as to verify if sexual dysfunction correlates with urinary symptoms and overall neurological impairment. From January 2001 to April 2004, 218 HTLV-I carriers (111 male and 107 female subjects) had complete clinical, neurological, and urological evaluation. They were assessed using standardized questionnaires to determine urinary complaints (Urinary Distress Inventory) and ED (Brief Male Sexual Function Inventory). Neurological impairment was established by Expanded Disability Status Scale (EDSS) from 0 to 10. HAM/TSP was considered as EDSS> or =2. A total of 17 males had clinically defined HAM/TSP (group 1). From the 94 HTLV-I-infected males, 62 were selected (group 2) and paired by age with patients in group 1. A total of 79 individuals were selected for this study. The age ranged from 35 to 81 y (mean=47.9+/-9.65). The percentage of ED in the studied population was 40.5%. In the HAM/TSP group, ED frequency was 88.2%. The associations among sexual dissatisfaction, erectile dysfunction, urinary symptoms (frequency, nocturia, and urgency) and EDSS> or =2 were statistically significant. In HAM/TSP, there is a slow and progressive degeneration of the lateral funiculus of the spinal cord. HTLV-I-infected individuals present a high frequency of ED and it is closely associated to urinary symptoms and the overall neurological picture. The HTLV-I carriers already had prominent compromise of the sexual activity.

Identification of clonally rearranged T-cell receptor beta chain genes in HTLV-I carriers as a potential instrument for early detection of neoplasia

We analyzed the genetic recombination pattern of the T-cell receptor beta-chain gene (TCR-beta) in order to identify clonal expansion of T-lymphocytes in 17 human T-lymphotropic virus type I (HTLV-I)-positive healthy carriers, 7 of them with abnormal features in the peripheral blood lymphocytes. Monoclonal or oligoclonal expansion of T-cells was detected in 5 of 7 HTLV-I-positive patients with abnormal lymphocytes and unconfirmed diagnosis by using PCR amplification of segments of TCR-beta gene, in a set of reactions that target 102 different variable (V) segments, covering all members of the 24 V families available in the gene bank, including the more recently identified segments of the Vbeta-5 and Vbeta-8 family and the two diversity beta segments. Southern blots, the gold standard method to detect T-lymphocyte clonality, were negative for all of these 7 patients, what highlights the low sensitivity of this method that requires a large amount of very high quality DNA. To evaluate the performance of PCR in the detection of clonality we also analyzed 18 leukemia patients, all of whom tested positive. Clonal expansion was not detected in any of the negative controls or healthy carriers without abnormal lymphocytes. In conclusion, PCR amplification of segments of rearranged TCR-beta is reliable and highly suitable for the detection of small populations of clonal T-cells in asymptomatic HTLV-I carriers who present abnormal peripheral blood lymphocytes providing an additional instrument for following up these patients with potentially higher risk of leukemia.

Long‐term serological outcome of infants who received frozen–thawed milk from human T‐lymphotropic virus type‐I positive mothers

Human T-lymphotropic virus type-I (HTLV-I) infection occurs via mothers' milk during feeding. However, freeze-thaw processing can eliminate the infectivity of the mother's milk of HTLV-I carriers. A long-term follow-up survey was conducted to investigate the HTLV-I infectivity of frozen-thawed mothers' milk among infants whose mothers were HTLV-I seropositive. Infants fed frozen-thawed mothers' milk did not become HTLV-I antibody-positive up until 1 year old, and all children followed up until an age of 11-12 years were antibody negative. This study showed that freeze-thaw processing can eliminate the HTLV-I infectivity of mothers' milk, and that HTLV-I carriers can indirectly feed their infants using frozen-thawed mothers' milk as a way to prevent HTLV-I infection.

Human T-lymphotropic virus type-I infection, survival and cancer risk in southwestern Japan: a prospective cohort study.

This study prospectively evaluated the associations of human T-lymphotropic virus type-I (HTLV-I) infection with survival and cancer incidence. The study base comprised 4297 adults (aged 40-69 years in 1993) who had either visited the outpatient clinic or who had received annual health check-ups at the A Hospital, Nagasaki, Japan, between 1985 and 1992 (HTLV-I seropositivity = 24.7%). During the follow-up period (1993-1999 or 2000), 290 deaths and 261 cases of malignant neoplasms occurred, including ten deaths and six incident cases of adult T-cell leukemia/lymphoma (ATL). After adjustment for gender, age and other covariates, HTLV-I seropositivity was associated with an increased mortality from all-causes excluding ATL (rate ratio, RR = 1.3, 95% confidence interval, CI = 1.0-1.7), all non-neoplastic diseases (RR = 1.5, 95% CI = 1.0-2.3) and heart diseases. HTLV-I infection was not found to be associated with an increased risk of developing total cancers other than ATL (RR = 0.98, 95% CI = 0.74-1.3), colorectal cancers, liver cancer or lung cancer, but was associated with a reduced risk of gastric cancer (RR = 0.42, 95% CI = 0.17-0.99). HTLV-I infection is associated with increased mortality from all-causes excluding ATL and all non-neoplastic diseases. HTLV-I carriers may not be at increased general cancer risk, but at reduced risk of gastric cancer.

Complement-dependent cytotoxic antibodies to human T lymphotropic virus type I (HTLV-I)-infected cells in the sera of HTLV-I-infected individuals.

To investigate whether HTLV-I induces the development of complement-dependent cytotoxic antibodies in humans, sera of asymptomatic HTLV-I carriers and of patients suffering from tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) or adult T cell leukaemia (ATL) were used in a cytotoxicity assay against a panel of target cells. This panel included uninfected cell lines (CEM, Jurkat, Molt and H9), cell lines chronically infected with HTLV-I (MT2, MT4, C9IPL and HUT102), as well as lines H36 (H9 infected with HTLV-I), H9-IIIB (H9 infected with HIVms) and H9-MN (H9 infected with HIMVMN). HTLV-I+ sera induced lysis of H36 and of lines expressing HTLV-I antigens in the presence of rabbit complement, but did not lyse cells in presence of human complement. The HTLV-I+ sera also failed to lyse the HTLV-I- lines and H9 cells, suggesting that lysis was specific for HTLV-I. H36 cell lysis was prevented by IgG depletion of the sera and by dialysis of rabbit complement against EGTA or EDTA. Rabbit complement-dependent cytotoxic antibodies were present in the sera of 14/14 HTLV-I-infected individuals; the highest titres were predominantly found in the sera of the TSP/HAM patients. Such antibodies were also detected in 5/5 individuals coinfected with HIV-1 and HTLV-I, although no cytotoxic antibody could be found against HIV-infected cells. Vice versa, sera of HIV-1-infected individuals did not exert a lytic effect in the presence of complement (of human or rabbit origin) against HIV-1- or HTLV-I-infected cells. Incubation of the sera of four HTLV-I-infected patients with HTLV-I env-specific synthetic peptides demonstrated that some of the complement-dependent cytotoxic antibodies recognized epitopes located on gp46 between amino acids 190 and 209. There is no correlation of rabbit complement-dependent cytotoxic HTLV-I antibodies with the development of disease.

Dysfunction of Dendritic and T Cells as the Cause of Immune Suppression in HTLV-I Infected Individuals

Human T lymphotropic virus type I (HTLV-I) impairs cellular immunity and can develop into adult T cell leukemia/lymphoma (ATLL). The Role of dendritic cells (DC) has not been fully elucidated in individuals infected by HTLV-I. To address this issue, we studied several cellular parameters, including phenotypic and functional characteristics of monocyte-derived DC. Generated DC exhibited down-regulation in the expression of CD1a and HLA-DR in HTLV-I carriers, suggesting partial impairment of maturation. T cells were stimulated by autologous DC in half of HTLV-I carriers, as well as healthy donors, but not in ATLL patients. Because of the importance of CD40-CD40 ligand (CD40L) signaling in establishing an inflammatory immune response, we also investigated the expression of soluble CD40L (sCD40L) of PHA-activated lymphocytes from HTLV-I infected individuals. sCD40L was detected in the culture supernatant of lymphocytes from one of four HTLV-I carriers investigated. These results suggest that the defect or aberration in the function of DC and the expression of sCD40L in T cells is associated with immune suppression in HTLV-I infected individuals.

Intrafamilial transmission and risk assessment of HTLV-I among blood donors in southern Taiwan.

The human T-lymphotropic virus type I (HTLV-I) is one of the important etiological agents of adult T-cell leukemia/lymphoma and of HTLV-I associated myelopathy or tropical spastic paraparesis. There is still a lack of data concerning HTLV-I transmission by seropositive carriers in Taiwan. We investigated the patterns of HTLV-I intrafamilial transmission in HTLV-I seropositive blood donors and assessed the risk factors of HTLV-I transmission in relatives of HTLV-I carriers in Taiwan. A total of twenty HTLV-I seropositive donors and their 103 relatives were enrolled. Among those 103 relatives, 40 (38.8%) were seropositive for HTLV-I. Their ages ranged from one to 70 years old with a mean age of 31.0 +/- 1.65 year-old. Three of the ten wives of male carriers were HTLV-I seropositive. However, none of the six husbands of female carriers were HTLV-I seropositive. Mother-to-child vertical transmission was found in nine of 48 (18.8%) tested. Significant risk factors of HTLV-I transmission among relatives of HTLV-I carriers were hospital admission, previous transfusion, breast feeding, anti-HCV seropositivity and female relatives of age >/= 30 with odds ratio (OR) of 9.73, 8.64, 4.36, 8.86 and 4.91, respectively (all p < 0.05). Nonsignificant risk factors of HTLV-I transmission were sharing needles, operation history, HBsAg seropositivity and male relatives of age >/= 30. Our findings suggest that mother-to-child and husband-to-wife transmissions are the important forms of intrafamilial transmission of HTLV-I in Taiwan. Screening for HTLV-I in family members of HTLV-I seropositive blood donors may be warranted.

Sex-specific mortality from adult T-cell leukemia among carriers of human T-lymphotropic virus type I.

Perinatal infection with human T-lymphotropic virus type I (HTLV-I) is considered a risk factor for adult T-cell leukemia (ATL). Incidence of ATL in Japan is generally higher in males compared with females, perhaps partly due to an earlier average age of infection among males. We estimated sex-specific ATL mortality among perinatally-infected HTLV-I carriers in the prospective Miyazaki Cohort Study in Japan. Based on the approximated proportion of perinatally-infected carriers, the relative risk (RR) of ATL for males compared with females was calculated. Six ATL deaths (4 males, 2 females) occurred among the 550 HTLV-I carriers in the cohort during 13 years of follow-up. The overall ATL mortality was 190.5 (95% CI 51.9-487.7) per 10(5) person-years for males and 51.7 (6.3-186.8) per 10(5) person-years for females (age-standardized RR = 3.9, p=0.02). By approximating the number of persons who acquired infection perinatally, the estimated mortality among those perinatally-infected HTLV-I carriers was 209.1 (57.0-535.2) per 10(5) person-years for males and 60.9 (7.4-219.9) per 10(5) person-years for females (age-standardized RR = 3.7, p=0.02). The adjusted RR changed minimally from the unadjusted RR, suggesting that earlier age of infection alone is unlikely the explanation for the male predominance in ATL. Based on the small number of cases available for analysis, aspects of gender itself appear to play a role in the development of this malignancy.