Human T-cell Lymphotropic Virus Type I Carriers Research Articles

Association of IL-10 Gene Polymorphisms and Human T Lymphotropic Virus Type I-Associated Myelopathy/tropical Spastic Paraparesis in North-East of Iran (Mashhad).

The underlying mechanisms leading to the development of human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals are not fully understood. Host genetic factors appear to be involved as risk factors for developing HAM/TSP. We investigated the possible contribution of interleukin-10 (IL-10) as a risk factor to HAM/TSP by comparing frequencies of promoter region single nucleotide polymorphisms in HTLV-I infected Iranian patients who either remained asymptomatic or developed HAM/TSP and asymptomatic HTLV-I carriers. Healthy, uninfected individuals from the same region served as healthy controls. Significant differences were observed in the distribution of IL-10 promoter alleles and genotypes at position -819 and -592 between HAM/TSP patients and healthy controls (P=0.01), and between HTLV-I carriers and healthy controls (P=0.02). The frequency of the low IL-10 producer haplotype (-1082*A, -819*T, -592*A) was significantly associated with HTLV-I carriage or HAM/TSP compared with healthy controls (P=0.02 and 0.01, respectively). Our results suggest that IL-10 -819*T and -592*A alleles are significant risk factors for developing HTLLV-I infection but do not appear to convey additional risk for developing HAM/TSP.

Telomere Disfunction Is Not An Early Genetic Event in Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm of post-thymic lymphocytes linked to human T-cell lymphotropic virus type I (HTLV-I). ATL develops in 3–5% of HTLV-I carriers after a long period of clinical latency and presents chromosomes abnormalities resulting in aneuploidy usually seem in telomere dysfunction disease. We were interested whether the abnormalities of the telomere regulation in ATL and if its abnormalities are correlated with ATL pathogenesis. The telomere length of TCD4 and TCD8 lymphocytes in samples from HTLV-I carriers (n= 52) with median age of 49.5 years (18–71 years) and ATL patients (n= 6) with median of 39 years (18–59 years) were assessed by fluorescence in situ hybridization and flow cytometry (Flow-FISH) and compared with healthy subjects (n = 58) matched for gender and age. We did not detected significant difference the telomere length of the TCD4 and TCD8 lymphocytes between HTLV-I carriers and health subjects. However we showed an accentuated loss in telomere length of the malignant T lymphocyte in ATL disease and values closed to those ageexpected in non-malignant T lymphocyte in ATL disease. We concluded that these results do not support a major role of telomere disfunction as an early event in pathogenesis of the ATL.

Urinary Symptoms Associated with Human T-Cell Lymphotropic Virus Type I Infection: Evidence of Urinary Manifestations in Large Group of HTLV-I Carriers

To describe the frequency of urologic manifestations in human T-cell lymphotropic virus type I (HTLV-I) seropositive individuals from Salvador and other cities in Bahia, Brazil, with or without clinical HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A total of 218 HTLV-I seropositive subjects referred from blood banks or neurologic clinics were admitted to the HTLV-I multidisciplinary outpatient clinic from January 2001 to April 2004. They were assessed using a standardized questionnaire to determine urinary complaints and quality of life. Neurologic impairment was established using the Expanded Disability Status Scale (EDSS). HAM/TSP was considered as an EDSS score of 2 or greater. Nocturia (35.8%) was the most frequent finding, followed by incontinence (29.8%), urgency (25.2%), frequency (22.0%), and dysuria (15.6%). Differences were found between individuals with an EDSS score of 0 and those with an EDSS score greater than 0 but less than 2 regarding frequency, nocturia, urgency, urinary loss of any degree, and quality of life. Dysuria and great or total urinary loss were more frequent among those with severe HAM/TSP (EDSS score greater than 6). Even HTLV-I subjects considered not to have HAM/TSP may have prominent urinary findings already present. Urologic manifestations, including nocturia and urinary loss, might be early manifestations of neurologic disease in those with HTLV-I.

Human T-cell lymphotropic virus type I (HTLV-I) proviral DNA viral load among asymptomatic patients and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis

To evaluate the human T-cell lymphotropic virus type I (HTLV-I) proviral DNA load among asymptomatic HTLV-I-infected carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), real time PCR using TaqMan probes for the pol gene was performed in two million peripheral blood mononuclear cells (PBMC). The albumin gene was the internal genomic control and MT2 cells were used as positive control. The results are reported as copies/10,000 PBMC, and the detection limit was 10 copies. A total of 89 subjects (44 HAM/TSP and 45 healthy HTLV-I-infected carriers) followed up at the Institute of Infectious Diseases "Emilio Ribas" and in the Neurology Division of Hospital of Clínicas were studied. The asymptomatic HTLV-I-infected carriers had a median number of 271 copies (ranging from 5 to 4756 copies), whereas the HAM/TSP cases presented a median of 679 copies (5-5360 copies) in 10,000 PBMC. Thus, HAM/TSP patients presented a significantly higher HTLV-I proviral DNA load than healthy HTLV-I carriers (P = 0.005, one-way Mann-Whitney test). As observed in other persistent infections, proviral DNA load quantification may be an important tool for monotoring HTLV-I-infected subjects. However, long-term follow-up is necessary to validate this assay in the clinical setting.

HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia

In the pathogenesis of adult T cell leukemia (ATL), an oncogenetic role of the human T cell lymphotropic virus type I (HTLV-I) Tax protein, viral escape from the host immune system, and host genetic changes have been proposed as contributory factors. We examined the premature stop codons in tax gene as one of the mutations that may lead to escape of HTLV-I from the cytotoxic T lymphocyte (CTL) response in HTLV-I carriers, to test whether a putative CTL escape mutant can emerge in the early stage of ATL development and whether HTLV-I infected cells with such a mutation can proliferate subsequently. We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations. The premature stop codon in tax gene existed in many non-ATL HTLV-I carriers as a minor population but not in the commonest HTLV-I sequence of the individual. This minor population with a premature stop codon did not expand subsequently in 3 asymptomatic carriers tested. There were cases who had a mutation or deletion in HTLV-I who also have either deletion of INK4 genes or mutation in p53 gene. Our findings suggest that CTL escape mutation can occur at an early stage of ATL development, and that certain host genetic changes favor the development of the aggressive form of ATL.

Human T Cell Lymphotropic Virus Type I (HTLV-I) p12IIs Dispensable for HTLV-I Transmission and Maintenance of Infection in Vivo

The function of the p12(I) protein of human T cell lymphotropic virus type I (HTLV-I) has been under debate. p12K (lysine) and p12R (arginine) variants of this protein at amino acid 88 and a shorter life of p12K had been reported by another group. Because HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients usually have a higher provirus load than asymptomatic HTLV-I carriers (ACs), and p12(I) had been suggested to confer a proliferative effect on HTLV-I-infected cells in vitro, it is possible that the relatively unstable p12K is less frequent in HAM/TSP patients than in ACs. To elucidate whether p12K and other alterations in the p12 gene were related to the outcome of HTLV-I infection, we sequenced the p12 gene in 144 HAM/TSP patients, 41 adult T cell leukemia (ATL) patients, and in 46 ACs. p12K was observed in only two HAM/TSP patients, but was not present in either ATL patients or ACs. Interestingly, a premature termination codon in the p12 was observed in 5.6% of HAM/TSP patients and in 4.9% of ATL patients but none was found in ACs. The p12 initiation codon was destroyed in one HAM/TSP patient. These HTLV-I variants with truncated p12 protein or with a destroyed initiation codon in the p12 gene appeared to have been transmitted in the subjects' families. These findings suggest that p12 is dispensable for the transmission and maintenance of HTLV-I infection, although it is premature to conclude that sequence varitation in the p12 gene is associated with differences in the outcome of HTLV-I infection.

Different cytokine production in tax-expressing cells between patients with human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis and asymptomatic HTLV-I carriers.

Human T cell lymphotropic virus type I (HTLV-I) provirus load has been reported to be generally higher in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) than in asymptomatic HTLV-I carriers (ACs). However, some ACs have a high HTLV-I provirus load comparable with that in patients with HAM/TSP. To examine whether other factors influence the outcome of HTLV-I infection in patients with HAM/TSP and ACs, we analyzed spontaneous Tax expression and cytokine production in peripheral blood mononuclear cells using flow cytometry. The Tax expression in HTLV-I-infected cells (percentage of Tax expressing cells/HTLV-I provirus load when assumed 1 copy/cell) and the intensity of Tax expression did not differ between these 2 groups. However, the production of interferon-gamma and tumor necrosis factor-alpha in Tax-expressing cells was significantly lower in ACs with high HTLV-I provirus load than in patients with HAM/TSP. This result suggests that the production of inflammatory cytokines in Tax-expressing cells is one of the factors that contribute to the development of HAM/TSP.

MRI Contributes to the Differentiation Between MS and HTLV-I Associated Myelopathy in British Columbian Coastal Natives

Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in British Columbian Coastal Natives has, to date, been a clinical and laboratory diagnosis. However, magnetic resonance imaging (MRI) abnormalities have been well-described in other populations in which HAM/TSP is endemic. In order to assess the usefulness of MRI as a diagnostic tool in this population, we compared scans of HAM/TSP patients with those of HTLV-I positive non-HAM/TSP British Columbian Coastal Natives (carriers) and multiple sclerosis patients presenting with progressive paraparesis. The typical nonspecific findings of thoracic cord atrophy and increased signal in the periventricular and subcortical white matter on T2-weighted images were confirmed in the HAM/TSP patients. Despite a lack of specificity of the MRI findings between HAM/TSP patients and HTLV-I carriers, criteria that could effectively differentiate HAM/TSP patients from multiple sclerosis patients with similar clinical presentations were determined. Clinical and radiological correlations suggest that longitudinal MRI investigations charting the course of HAM/TSP may reveal the clinical significance of these lesions and further define the role of MRI in the diagnosis of this entity. Magnetic resonance imaging is an important supplement to immunological and clinical data in differentiating multiple sclerosis from HAM/TSP.

Tumor necrosis factor, tumor necrosis factor receptors type 1 and 2, lymphotoxin-α, and HLA-DRB1 gene polymorphisms in human T-Cell lymphotropic virus type I associated myelopathy

We studied tumor necrosis factor (TNF), lymphotoxin-α (LT-α), and TNF receptors type 1 (TNFR-1) and type 2 (TNFR-2) gene polymorphisms as well as HLA class II DRB1 alleles in Japanese patients with human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) ( n = 51), patients with adult T-cell leukemia/lymphoma (ATL) ( n = 48), asymptomatic HTLV-I carriers ( n = 50), and HTLV-I seronegative, normal controls ( n = 112). There were significant differences between HAM patients and normal controls in the distributions of TNF promoter region polymophism at position −857, the LT-α gene NcoI polymorphism, and the T-G substitution in exon 6 of the TNFR-2 gene. The distribution of the NcoI polymorphism of the LT-α gene was also significantly different between HAM patients and asymptomatic HTLV-I carriers. In contrast, we failed to detect any difference in the frequency of DRB1, TNF promoter at position −1031, −863, or the TNFR-1 promoter −383 polymorphism. The results suggest that the TNF/LT-α gene region within the HLA class III of chromosome 6 and the TNFR-2 gene region located on chromosome 1p36 might contribute to susceptibility to HAM, and that aberrant expression or function of these cytokines and the receptor could be involved in the development of HAM.

Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan.

The incidence of adult T-cell leukemia/lymphoma (ATL) and its impact on that of total non-Hodgkin lymphoma (NHL) were evaluated in Nagasaki, an area in southwestern Japan where human T-cell lymphotropic virus type I (HTLV-I) is endemic. The first study area comprised 4 towns located on the K Islands, which had a population of 26,870 in 1990. The overall HTLV-I seroprevalence estimated from the serologic survey of 18,485 subjects was 16.2%. By using the data from the Nagasaki Prefectural Cancer Registry (NPCR) and reviewing clinical and laboratory information, we identified 40 cases of ATL and 35 cases of other NHL diagnosed between 1985 and 1995. The crude annual incidence of ATL among 100,000 HTLV-I carriers aged 30 or older was estimated at 137.7 for men and 57.4 for women, with a significant sex difference after adjustment for age (rate ratio = 2.50, 95% confidence interval 1.32-4.73). The cumulative risk from 30 to 79 years of age was estimated at approximately 6.6% for men and 2.1% for women. Among the entire population, ATL accounted for 51 to 59% of the total NHL incidence, showing the strong impact of HTLV-I infection. The second study area comprised the whole of Nagasaki Prefecture (total population in 1990 = 1.56 million). Between 1985 and 1995, 989 cases of ATL and 1,745 cases of other NHL were registered in the NPCR. The world age-standardized annual incidence rate of ATL per 100,000 persons aged 30 or older was estimated at 10.5 for men and 6.0 for women, which accounted for approximately 37 to 41% of the total NHL incidence.

Polymorphism of the 5'-flanking region of the tumor necrosis factor (TNF)-alpha gene and susceptibility to human T-cell lymphotropic virus type I (HTLV-I) uveitis.

The genetic background of human T-cell lymphotropic virus type I (HTLV-I) uveitis (HU) was investigated by studying the distribution of 5 polymorphisms of the 5'-flanking promoter/enhancer region of the tumor necrosis factor (TNF)-alpha gene in patients with HU, together with patients with adult T-cell leukemia (ATL), asymptomatic HTLV-I carriers, and healthy controls. The frequencies of the -1,031C allele (T-->C transition at position -1,031) and -863A allele (C-->A transition at position -863) in the HU patients, but neither in the ATL patients nor in the carriers, were significantly higher than those in the controls. The -1,031C and -863A alleles, in the absence of the HLA B61 or the DRB1*0901 allele which is in linkage disequilibrium with these alleles, were associated with increased susceptibility to HU. These results suggest that the -1,031C and -863A alleles might be genetic risk factors for HU.

Vertical transmission of HTLV-I/II: a review.

The vertical transmission of the human T-cell lymphotropic virus type I (HTLV-I) occurs predominantly through breast-feeding. Since some bottle-fed children born to carrier mothers still remain seropositive with a frequency that varies from 3.3% to 12.8%, an alternative pathway of vertical transmission must be considered. The prevalence rate of vertical transmission observed in Japan varied from 15% to 25% in different surveys. In Brazil there is no evaluation of this form of transmission until now. However, it is known that in Salvador, Bahia, 0.7% to 0.88% of pregnant women of low socio-economic class are HTLV-I carriers. Furthermore the occurrence of many cases of adult T-cell leukemia/lymphoma and of four cases of infective dermatitis in Salvador, diseases directly linked to the vertical transmission of HTLV-I, indicates the importance of this route of infection among us. Through prenatal screening for HTLV-I and the refraining from breast-feeding a reduction of approximately 80% of vertical transmission has been observed in Japan. We suggest that in Brazil serologic screening for HTLV-I infection must be done for selected groups in the prenatal care: pregnant women from endemic areas, Japanese immigrants or Japanese descendents, intravenous drug users (IDU) or women whose partners are IDU, Human immunodeficiency virus carriers, pregnant women with promiscuous sexual behavior and pregnant women that have received blood transfusions in areas where blood donors screening is not performed. There are in the literature few reports demonstrating the vertical transmission of HTLV-II.

Human leukocyte antigen class II alleles associated with human T-cell lymphotropic virus type I infection and adult T-cell leukemia/lymphoma in a Black population.

Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM; also known as tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder. Worldwide, several million HTLV-I carriers are at risk for disease, with an estimated lifetime cumulative risk of 1%-5%. However, the determinants of disease progression are relatively unknown. We studied human leukocyte antigens (HLA class II) that have been implicated in the pathogenesis of HTLV-I-related diseases. We analyzed HLA class II alleles among asymptomatic HTLV-I carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I seronegative control subjects (n = 51). All participants were of African descent and were enrolled in epidemiologic studies conducted at the University of the West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays for HLA antigen serotyping and polymerase chain reaction-based methods to examine HLA class II DRB1 and DQB1 alleles. Two antigens determined by serotyping, DR15 and DQ1, occurred at significantly increased frequency among HTLV-I carriers compared with seronegative control subjects (42% versus 22% for DR15 [odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.0-7.2] and 78% versus 53% for DQ1 [OR = 3.1; 95% CI = 1.2-8.5]). Asymptomatic carriers were shown to have an HLA class II allele distribution similar to that of patients with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602 were significantly greater in patients with ATL and asymptomatic carriers than in patients with HAM/TSP. In addition, haplotypes DRB1*1101-DQB1*0301 and DRB1*1501-DQB1*0602 were significantly increased among patients with ATL compared with patients with HAM/TSP. These data suggest that host genetic background is an important factor in determining whether HTLV-I carriers develop either ATL or HAM/TSP.

Intrafamilial transmission of HTLV-I and its association with anti-Tax antibody in an endemic population in Japan.

To assess the relationship of anti-Tax antibody to human T-cell lymphotropic virus type-I (HTLV-I) transmission, the sero-prevalence of HTLV-I was analyzed among married couples and among mother/child (both adults) pairs. HTLV-I seroprevalence was significantly higher among wives with anti-Tax+ than those with anti-Tax- HTLV-I carrier husbands (82.4% vs. 59.5%). However, in the group of wives aged 60 years or older, there was no statistical difference in HTLV-I seropositivity based on the husbands' anti-Tax sero-status. In the group whose wives were less than 60 years old, more anti-Tax sero-positive than sero-negative husbands had high DNA levels (57.1% and 20.0%), whereas in the group of husbands whose wives were aged 60 years or older, the number of anti-Tax sero-positive and sero-negative individuals with high DNA levels was similar. HTLV-I sero-prevalence was significantly higher among the adult men with anti-Tax+ carrier mothers than those with anti-Tax- carrier mothers (52.0% vs. 14.3%). For women, HTLV-I sero-prevalence did not differ significantly according to their mothers' anti-Tax sero-status. Our results suggest that the presence of anti-Tax antibody in HTLV-I carriers is an age-dependent risk factor for male-to-female HTLV-I transmission. Furthermore, the effect of the mother's anti-Tax antibody as a risk factor for vertical HTLV-I transmission could be observed in men even after becoming adults.

Clonal integration and expression of human T‐cell lymphotropic virus type I in carriers detected by polymerase chain reaction and inverse PCR

Adult T-cell leukemia (ATL) is a neoplasm of mature helper (CD4) T lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) has been suggested to be the causative virus of ATL. HTLV-I integrates its proviruses into random sites in host chromosomal DNA. Clonal integration has been observed in patients with ATL, including smoldering, chronic, and acute states. However, random and/or polyclonal integration has only been reported in a few asymptomatic HTLV-I carriers. To clarify the clonality of HTLV-I-infected cells in carriers, we used an inverse polymerase chain reaction (IPCR), which is more sensitive than Southern blot analysis. We used the peripheral blood momonuclear cells (PBMC) from 16 asymptomatic carriers and the separated CD4-positive cells. No cases showed either a monoclonal or polyclonal integration of the HTLV-I provirus by Southern blot. But, using IPCR, 7 of 16 cases showed either mono- or oligoclonal integration. In addition, the populations of clonal provirus in the total PBMC were frequently different from those in the CD4-positive cells. Three cases showed expression of HTLV-I tax/rex mRNA in the total PBMC, but no such expression was found in CD4-positive cells. In this study, an unexpected frequency of clonal HTLV-I provirus DNA was observed in HTLV-I carriers. These findings indicate that the clonal but nonmalignant proliferation of HTLV-I-infected cells already occurs even in HTLV-I carriers, and therefore that some other step is necessary to induce malignant proliferation. Am. J. Hemato. 54:306–312, 1997. © 1997 Wiley-Liss, Inc.

Clonal integration and expression of human T-cell lymphotropic virus type I in carriers detected by polymerase chain reaction and inverse PCR.

Adult T-cell leukemia (ATL) is a neoplasm of mature helper (CD4) T lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) has been suggested to be the causative virus of ATL. HTLV-I integrates its proviruses into random sites in host chromosomal DNA. Clonal integration has been observed in patients with ATL, including smoldering, chronic, and acute states. However, random and/or polyclonal integration has only been reported in a few asymptomatic HTLV-I carriers. To clarify the clonality of HTLV-I-infected cells in carriers, we used an inverse polymerase chain reaction (IPCR), which is more sensitive than Southern blot analysis. We used the peripheral blood momonuclear cells (PBMC) from 16 asymptomatic carriers and the separated CD4-positive cells. No cases showed either a monoclonal or polyclonal integration of the HTLV-I provirus by Southern blot. But, using IPCR, 7 of 16 cases showed either mono- or oligoclonal integration. In addition, the populations of clonal provirus in the total PBMC were frequently different from those in the CD4-positive cells. Three cases showed expression of HTLV-I tax/rex mRNA in the total PBMC, but no such expression was found in CD4-positive cells. In this study, an unexpected frequency of clonal HTLV-I provirus DNA was observed in HTLV-I carriers. These findings indicate that the clonal but nonmalignant proliferation of HTLV-I-infected cells already occurs even in HTLV-I carriers, and therefore that some other step is necessary to induce malignant proliferation.

The association of antibodies against human T cell lymphotropic virus type I (HTLV-I) pX gene mutant products with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Antibodies specific for the products of the human T cell lymphotropic virus type I (HTLV-I) pX frame-shift mutants were studied by ELISA. The serum IgG antibodies to the synthetic peptide corresponding to one nucleotide insertion at position 7784 were significantly more common in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in HTLV-I carriers who had neither HAM/TSP nor adult T cell leukemia (39% vs. 5%). The seropositivities to the other synthetic peptides, which corresponded to the one nucleotide deletion at position 7475 and the internal deletion of nt 7754-7819 and nt 7853-7936, were rare. A genetic study confirmed the presence of the responsible mutation of the pX gene in peripheral blood mononuclear cells and central nervous system tissue from HTLV-I-infected subjects with and without HAM/TSP. These results suggest that HTLV-I pX frame-shift mutants are expressed in vivo in HTLV-I carriers; they also induce antibodies. especially in those with HAM/TSP.

HTLV-I uveitis.

Human T-cell lymphotropic virus type I (HTLV-I) is known to cause adult T-cell leukemia/T-cell lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. Recent seroepidemiologic, clinical, and virologic studies indicate that the virus is also related to a certain type of uveitis, which has been classified as uveitis without defined etiologies or idiopathic uveitis. According to the seroepidemiologic survey, the seroprevalence of HTLV-I in patients with idiopathic uveitis was significantly higher than that of two control groups, that is, patients with uveitis with defined etiologies and patients with nonuveitic ocular diseases. Clinically, the uveitis seen in HTLV-I carriers is characterized by moderate to severe cellular infiltration in the eye and by moderate retinal vasculitis, and the intraocular inflammation responds well to corticosteroid therapy. Interestingly, 25% of female patients with the disease had a previous history of Graves disease with hyperthyroidisms. The following virologic, molecular biologic findings suggest that cytokines produced by HTLV-I-infected T cells in the eye play the central role in the pathogenic mechanisms of the uveitis: (a) the virus load in the peripheral blood monocytes analyzed by the quantitative polymerase chain reaction methods was significantly greater in patients with the uveitis than in asymptomatic carriers, (b) the proviral DNA of HTLV-I and the gene expression of the virus at the mRNA level was detected in the infiltrating cells from the eyes of the patients, (c) the virus particles were detected by electron-microscopic examination in the T-cell clones established from the intraocular fluid of the patients, and (d) the HTLV-I-infected T cells produced a variety of cytokines without any stimuli, such as interleukin (IL)-1 alpha, IL-2, IL-3, IL-6, IL-8, IL-10, tumor necrosis factor alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Based on the seroepidemiologic, clinical, and virologic data, the uveitis seen in HTLV-I carriers is considered to be a distinct clinical entity related to HTLV-I infection, and the disease is designated as HTLV-I uveitis.

Limited TCR Vβ Usage of Infiltrating T cells in Synovial Tissues from Patients with HTLV-I Associated Arthropathy

Human T cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of adult T cell leukemia/lymphoma and recently has also been suggested to be involved in chronic arthritis. The synovia of patients with rheumatoid arthritis (RA) contains activated T lymphocytes, with a restricted expression of T cell receptor (TCR) variable (V) beta gene segments. To characterize the T-cell populations of RA among HTLV-I carriers and noncarriers, we performed the immunohistochemical staining of CD4 and CDB, as well as a reverse transcription polymerase chain reaction (RT-PCR) to estimate the proportion of TCR beta RNA containing any particular V elements on the synovial specimens. In all but one HTLV-I carrier, the proviral DNA and/or RNA expression of HTLV-I was detected in the synovium. The CD4-positive cells proliferated markedly in the HTLV-I carriers compared with the noncarriers. In contrast to mononuclear cells in the peripheral blood, synovial T cells expressed only a few V beta transcripts, and no definite difference was observed between the carriers and the noncarriers. These results suggest that a common major antigen associated with the pathogenesis of RA may thus selectively interact with the V beta component of the TCR. Using RT-PCR, we studied the expression of the recombination-activating gene-1 (RAG-1), which was used in the V(D)J recombination of immunoglobulin and TCR genes. In all cases, RAG-1 was transcripted. The results supported the possibility that the extrathymic development of the selected TCR V beta T cells occurred in the synovia.

A novel diagnostic method of adult T-cell leukemia: monoclonal integration of human T-cell lymphotropic virus type I provirus DNA detected by inverse polymerase chain reaction

Adult T-cell leukemia (ATL) is neoplasm of the mature helper T lymphocytes and human T-cell lymphotropic virus type-I (HTLV-I) has been shown to be causative virus of ATL. Because HTLV-I integrates its provirus randomly into host chromosomal DNA, monoclonal integration of HTLV-I provirus indicates the clonal proliferation of HTLV-I-infected cells. Therefore, demonstration of clonality of HTLV-I proviral DNA is essential to diagnosis of ATL. Southern blot analysis was used for this purpose. We developed the novel method using inverse polymerase chain reaction (IPCR) to detect the clonality of HTLV-I proviral DNA. This method identified the clonality in all ATL cases. Diagnosis could be made within 3 days using this method. It enabled us to detect specifically the presence of minimal numbers of ATL cells with high sensitivity. It also identified the monoclonal or oligoclonal proliferations of HTLV-I-infected cells in HTLV-I carriers and the intermediate state, in which no clonality could be shown by conventional Southern blot analyses. This finding indicated that even HTLV-I carriers had monoclonal proliferation of HTLV-I-infected cells without any symptoms. This novel method is shown to be useful for the diagnosis of ATL and provides information on the natural course of HTLV- I infection.