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.     

Angiocentric T-cell lymphoma associated with human T-cell lymphotropic virus type I infection

We describe two patients who presented with vasculitic, ulcerative skin lesions that had the histologic features of lymphomatoid granulomatosis or angiocentric T-cell lymphoma. These patients were found to have antibodies to human T-cell lymphotropic virus type I.     

Prospects for the management of human T-cell lymphotropic virus type 1-associated myelopathy

Over the twenty-five years since the association of human T-cell lymphotropic virus type 1 infection with tropical spastic paraparesis, little progress has been made in the treatment of this chronic debilitating condition. The purpose of this review is to highlight the most informative results and to identify the most promising candidates for further study. Although many small observational studies have been reported, only twice have the positive data been tested in randomized controlled studies. In the first study, interferon-alpha 3 MU was found to be better than 0.3 or 1 MU over four weeks, whilst zidovudine plus lamivudine performed no better than placebo after 24-48 weeks of therapy in the second study. Preliminary data from studies of immunomodulatory therapy including cyclosporine and monoclonal antibodies to CD25 and interleukin-15 are encouraging and further comparative studies are indicated with the combination of antiretroviral therapy with histone deacetylation inhibition, which has been shown to reduce simian T-lymphotropic virus type 1 proviral load in baboons, unless this proves unsuccessful in human T-cell lymphotropic virus type 1 infection.     

Association between interleukin-6 gene polymorphism and human T-cell leukemia virus type I associated myelopathy

We studied cytokine gene polymorphisms in the promoter region, including interleukin (IL)-6, IL-1beta, and IL-10, in Japanese patients with human T-cell leukemia virus type I (HTLV-I) associated myelopathy (HAM) (n = 65), asymptomatic HTLV-I carriers (n = 143), and HTLV-I seronegative, normal controls (n = 160). There was a significant difference between HAM patients and HTLV-I carriers in the distribution of IL-6 promoter polymorphism at position -634 (chi(2) = 9.90, p = 0.0071). The IL-6 genotype was also significantly different between HAM patients and normal controls (chi(2) = 11.53, p = 0.0033), while a similar distribution was observed in IL-1beta and IL-10 polymorphisms among HAM patients, carriers, and normal controls. The results suggest that IL-6 gene region may contribute to susceptibility to HAM, and that aberrant cytokine productions could be involved in the development of HAM.     

Mother-to-child transmission of human T-cell lymphotropic virus type I associated with prolonged breast-feeding

OBJECTIVES: We assessed the risk of transmitting human T-cell lymphotropic virus type I (HTLV-I) through breast-feeding. STUDY DESIGN/METHODS: To assess the risk of mother-to-child transmission of HTLV-I, 212 HTLV-I-seropositive women and 145 HTLV-I-seronegative women were enrolled in a prospective cohort study conducted in Kingston, Jamaica. Their offspring were examined at regular intervals, and HTLV-I serostatus was determined at each visit. RESULTS: Twenty-eight of the 181 children with at least one postnatal visit born to HTLV-I-seropositive women (and none of the children born to HTLV-I-seronegative women) were persistently seropositive and were considered HTLV-I infected (Kaplan-Meier estimated cumulative incidence, 18%; 95% CI, 12%-24%). Among children observed for at least 24 months, 19 (32%) of 60 children breast fed for 12 months or longer were HTLV-I seropositive, compared with only 8 (9%) of 86 children breast-fed for less than 12 months (relative risk, 3.4; 95% CI, 1.7-6.9). Compared with children weaned at younger ages, transmission of HTLV-I was associated with continued breast-feeding of children who were 12 to 18 months of age (relative hazard, 6.4; 95% CI, 2.1-180.2) and older than 18 months (relative hazard, 18.1; 95% CI, 1.4-29.5). Transmission was also associated with higher maternal antibody titer (a possible marker of virus load), prolonged duration of ruptured membranes during childbirth, and lower maternal income. CONCLUSIONS: These results suggest that limiting the duration of breast-feeding to less than 12 months for children born to HTLV-I-seropositive mothers may significantly reduce mother-to-child transmission of HTLV-I.     

Establishing phenotypic features associated with morbidity in human T-cell lymphotropic virus type 1 infection

The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HT). Although it is widely believed that virus infection and host immune response are involved in the pathogenic mechanisms, the role of the immune system in the development and/or maintenance of HT remains unknown. We performed an analysis of the peripheral blood leukocyte phenotype for two different subcohorts of HTLV-1-infected individuals to verify the existence of similar immunological alterations, possible laboratory markers for HT. The leukocyte population balance, the activation status of the T lymphocytes, and the cellular migratory potential of T lymphocytes, monocytes, and neutrophils were evaluated in the peripheral blood of HTLV-1-infected individuals classified as asymptomatic individuals, oligosymptomatic individuals, and individuals with HT. Data analysis demonstrated that a decreased percentage of B cells, resulting in an increased T cell/B cell ratio and an increase in the CD8+ HLA-DR+ T lymphocytes, exclusively in the HT group could be identified in both subcohorts, suggesting its possible use as a potential immunological marker for HT for use in the laboratory. Moreover, analysis of likelihood ratios showed that if an HTLV-1-infected individual demonstrated B-cell percentages lower than 7.0%, a T cell/B cell ratio higher than 11, or a percentage of CD8+ HLA-DR+ T lymphocytes higher than 70.0%, this individual would have, respectively, a 12-, 13-, or 22-times-greater chance of belonging to the HT group. Based on these data, we propose that the T cell/B cell ratios and percentages of circulating B cells and activated CD8+ T lymphocytes in HTLV-1-infected patients are important immunological indicators which could help clinicians monitor HTLV-1 infection and differentiate the HT group from the asymptomatic and oligosymptomatic groups.     

Human T lymphotropic virus type I associated myelopathy with pulmonary and cutaneous lesions.

A necropsy case of human T lymphotropic virus I (HTLV-I) associated myelopathy (HAM) in a 64 year old man with serological and genetical confirmation of HTLV-I infection is reported. The spinal cord, lung, and skin were mainly affected. Severe degeneration had occurred in the spinal cord, not only in the lateral columns but also in the anterior and posterior columns. The degenerate lesions showed proliferation of capillaries, loss of myelin and axon, and perivascular and parenchymal infiltration with T lymphocytes and foamy macrophages in the white matter. T lymphocytes had infiltrated the lung and there was vascular proliferation in the peribronchus. OPD4 positive cells predominated in the lung. The patient also had erythrodermia where dense and bandlike HTLV-I infected lymphoid cell infiltration was observed, with mild atypia and epidermotropism. HTLV-I may cause multiorganic inflammatory disorders, although the definitive role of HTLV-I in the pathogenesis is still unknown.     

Detection of human T-cell lymphotropic virus type 1 in plasma samples

Human T-cell lymphotropic virus type 1 (HTLV-1) is an RNA virus responsible for diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATL). Cell-to-cell contact and Tax-induced clonal expansion of infected cells are the main modes of virus replication, making virus detection during the viremic stage difficult. Consequently, the proviral load is the current virologic marker for disease monitoring, but the mechanisms of progression have not been established yet. Thus, this study investigated the presence of virus in plasma from asymptomatic HTLV-1 carriers and from HAM/TSP patients. Real-time PCR was performed on DNA from 150 plasma samples; 12 (8%) had detectable DNA amplification, including 6 (4%) asymptomatic HTLV-1 carriers and 14 (26%) HAM/TSP patients (p < 0.005). Of the 33 samples submitted for nested PCR, six (18%, p = 0.02) were positive for HTLV-1 RNA in the plasma. Additionally, 26 plasma samples were treated with DNAse enzyme to eliminate any DNA contamination before RNA extraction. Two of them (8%) showed amplification for HTLV-1 (p = 0.5). Therefore, this study described for the first time the detection of free HTLV-1 RNA in plasma from HTLV-1-infected subjects, regardless of their clinical status. Thus, HTLV-1 viral replication does occur in plasma, and other transmission pathways for HTLV-1 should be investigated further.     

A cluster of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis in Jujuy,Argentina

Compared with other regions in Argentina, greater human T-cell lymphotropic virus type I (HTLV-I) seroprevalence has been reported in Jujuy Province, where it reaches 2.32% in the general population, so that a search for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases deserved to be carried out. Accordingly, a clinically diagnosed and serologically confirmed cluster of cases in 1 man and 10 women, including 2 sisters, is described here. Most patients (9/11) were born in Cochinoca Department, located in an Andes highland area called Puna Juje?a, situated at more that 3400 m above sea level. No history of risk factors was disclosed, except for a single transfusion in 1 patient. In contrast to the Andean region of Bolivia, where high HTLV-I seroprevalence is in part attributable to Japanese immigrants, the Jujuy population mainly consists of aborigines, mestizos, and European descendants. Therefore, the long-term presence of virus in Jujuy natives may be taken for granted. Considering the HAM/TSP cluster described here plus previously reported isolated cases in neighboring Salta Province, we speculate that the Puna Juje?a region and regions in that vicinity would be a microepidemic focus of disease. To determine the role of possible pathogenic cofactors such as geographic, ethnic, genetic, and cultural features, further pertinent surveys are required in subtropical northwestern Argentina.     

Genetic characterization and phylogeny of human T-cell lymphotropic virus type I from Chile

Infection with Human T-Cell Lymphotropic Virus type I (HTLV-I) have been associated with the development of the HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Phylogenetic analyses of HTLV-I isolates have revealed that HTLV-I can be classified into three major groups: the Cosmopolitan, Central African and Melanesian. In the present study, we analyzed the tax, 5' ltr, gag, pol, and env sequences of proviruses of PBMC from ten HAM/TSP patients to investigate the phylogenetic characterization of HTLV-I in Chilean patients. HTLV-I provirus in PBMC from ten Chilean patients with HAM/TSP were amplified by PCR using primers of tax, 5' ltr, gag, pol, and env genes. Amplified products of the five genes were purified and nucleotide sequence was determined by the dideoxy termination procedure. DNA sequences were aligned with the CLUSTAL W program. The results of this study showed that the tax, 5' ltr, gag, pol, and env gene of the Chilean HTLV-I strains had a nucleotide homology ranged from 98.1 to 100%, 95 to 97%, 98.9 to 100%, 94 to 98%, and 94.2 to 98.5% respect to ATK-1 clone, respectively. According to molecular phylogeny with 5' ltr gene, the Chilean HTLV-I strains were grouped with each other suggesting one cluster included in Transcontinental subgroup.     

Tumor necrosis factor gene polymorphisms in ankylosing spondyiitis

Abstract: Despite the strength of the association of ankylosing spondyiitis (AS) with HLA-B27, other genetic elements could play a possible role in the pathophysiology of AS. In view of its gene location, in the proximity of the HLA-B locus, and biological effects, tumor necrosis factor (TNF) genes are potential candidates for additive susceptibility factors to AS. TNFα and TNFβ genotypes were analyzed by PCR-RFLP in 57 patients with AS, 102 random controls and 30 HLA-B*27-positive controls. No significant differences of TNFα promoter variations at position -308 and -238 were found in AS patients in comparison with controls. The -244 polymorphism was not detected in our population. The TNFβ genotype frequency was significantly different between AS patients and random controls. However, when the distribution of the TNFβ genotype was compared in B*27-positive AS patients and controls, these differences disappeared. In addition, we demonstrated that the TNFβ*l was in strong linkage disequilibrium with the B*27 allele, which may explain the differences observed for the TNFβ genotype among AS patients and random controls. Our data suggest that the polymorphisms of TNFα and TNFβ genes do not have an independent effect on AS susceptibility.     

Purification of type I and type II tumor necrosis factor receptors from human lung tissue.

Two receptors for tumor necrosis factor-alpha (TNF) were purified from detergent-solubilized human lung tissues by adsorption to TNF-Sepharose, followed by elution with low pH. By SDS-PAGE analysis, the two proteins had molecular weights of 75 and 55 kD. Using a soluble receptor assay, a binding affinity of approximately 1.2 nM was calculated for the isolated lung receptors. Each protein, isolated by electroelution from polyacrylamide gels, specifically bound TNF. Antibodies raised against the mixture of type I and II receptors bound specifically to both purified receptors by immunoblot analysis. Both the 75- and 55-kD receptors could be precipitated from 125I-surface-labeled or 35S-methionine-labeled U937 cells using TNF-Sepharose or anti-receptor antibodies. In addition, the anti-TNF receptor antibodies partially blocked binding of TNF to U937 cells and specifically immunoprecipitated 125I-TNF cross-linked to its receptors on U937 cells. These results demonstrate that both type I and II TNF receptors can be isolated from human lung tissue by ligand affinity chromatography, and that U937 cells express both TNF receptor types.     

Geographical clustering of human T-cell lymphotropic virus type 1 infection in Honduras.

Geographical clustering of human T-cell lymphotropic virus type 1 (HTLV-1) infection has been identified in the nonmestizo communities in several cities along the Atlantic coast of Honduras. Of the 2,651 serum samples tested, 122 samples were repeatedly reactive for HTLV-1 antibodies in two different enzyme immunoassays and 3 were indeterminate. These sera did not react in the HTLV-2-specific antibody tests. The presence of HTLV-1 antibodies was confirmed by HTLV-1 immunoblots or Western blots (immunoblots), and the infection was verified by the detection of HTLV-1-specific genetic sequences in the cellular DNA by PCR. Genomic DNA from the peripheral blood mononuclear cells was first tested with generic primers and probes that identified both HTLV-1 and HTLV-2. Next, all DNA samples that showed HTLV reactivity were tested by PCR with specific primers and probes that distinguished HTLV-1 sequences from those of HTLV-2. Our results indicate that only HTLV-1 infection was present in the blood of both mestizo and nonmestizo residents of 15 cities in the Republic of Honduras. The overall prevalence of HTLV-1 infection in the nonmestizo population was 8.1% (95% confidence limit, 6.6 to 9.7%). The mestizo population residing in the same geographical vicinities showed a HTLV-1 antibodies in 0.5% of serum samples tested (95% confidence limit, 0.6 to 1.7%), indicating a significantly greater prevalence of HTLV-1 infection in the nonmestizo population than in the mestizo ethnic groups living in Honduras (P = 0.0001). Since no HTLV-2 antibody reactivity or HTLV-2-specific genetic sequences were detected by PCR with different primers and probes, it was concluded that HTLV-2 infection was not present in the Honduran population groups we tested. Our study also suggested an endemic nature for this virus because there was no difference in the prevalence rate of HTLV-1 antibodies in the nonmestizo community living in the coastal towns of Honduras between 1989 and 1993. This is the first report of HTLV-1 cluster identification in Honduras, Central America.     

Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections.

In serum, the enzyme adenosine deaminase (ADA) is known to be divided into two isoenzymes, ADA1 and ADA2, which have different molecular weights and kinetic properties. The present study investigated ADA isoenzyme levels in the sera of patients infected with retroviruses associated with adult T-cell leukemia (ATL), human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), and AIDS, ADA isoenzyme activities were found to be significantly (P < 0.001) higher in the sera of patients with ATL, HAM, and AIDS than in the sera of healthy controls. In the case of the ADA subtypes in the sera of patients with ATL, ADA1 activity was significantly (P < 0.001) elevated in patients with the acute and lymphoma types of ATL compared with that in patients with the chronic and smoldering types of ATL. ADA2 activity was significantly elevated in the sera of patients with the acute, lymphoma, and chronic types of ATL (P < 0.001) compared with that in patients with smoldering ATL and HTLV-1 carriers. In the case of patients with human immunodeficiency virus type 1 (HIV-1) infection, ADA1 and ADA2 activities in the sera of patients with AIDS and HIV-1 antibody-positive individuals were significantly (P < 0.001) higher than those in the sera of HIV-1 antibody-negative individuals. A significant elevation in ADA2 activity was also seen in the sera of AIDS patients (P < 0.01) compared with that in the sera of HIV-1 antibody-positive individuals. These results suggest that the magnitude of elevation of ADA isoenzyme levels in serum correlates well with the clinical conditions of the patients with these diseases. Measurement of the activities of ADA isoenzymes may therefore provide an additional parameter for distinguishing the subtypes of ATL and may prove to be useful as prognostic and therapeutic monitors in diseases associated with HTLV-1 and HIV-1 infections.     

Tumor necrosis factor induces tumor necrosis via tumor necrosis factor receptor type 1-expressing endothelial cells of the tumor vasculature

Activation of endothelial cells, fibrin deposition, and coagulation within the tumor vasculature has been shown in vivo to correlate with the occurrence of tumor necrosis factor (TNF)-induced tumor necrosis in mice. In the present study we investigated which target cells mediate the TNF-induced necrosis in fibrosarcomas grown in wild type (wt), TNF receptor type 1-deficient (TNFRp55-/-), and TNF receptor type 2-deficient (TNFRp75-/-) mice. TNF administration resulted in tumor necrosis exclusively in wt and TNFRp75-/-, but not in TNFRp55-/- mice, indicating a dependence of TNF-mediated tumor necrosis on the expression of TNF receptor type 1. However, using wt and TNFRp55-/- fibrosarcomas in wt mice, we found that TNF-mediated tumor necrosis was completely independent of TNF receptor type 1 expression in tumor cells. Thus we could exclude any direct tumoricidal effect of TNF in this model. Soluble TNF induced leukostasis in wt and TNFRp75-/- mice but not in TNFRp55-/- mice. TNF-induced leukostasis in TNFRp55-/- mice was restored by adoptive bone marrow transplantation of wt hematopoietic cells, but TNF failed to induce tumor necrosis in these chimeric mice. Because TNF administration resulted in both activation and focal damage of tumor endothelium, TNF receptor type 1-expressing cells of the tumor vasculature, likely to be endothelial cells, appear to be target cells for mediating TNF-induced tumor necrosis.     

Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-alpha polymorphisms on type 1 diabetes susceptibility

 Tumor necrosis factor (TNF) and lymphotoxin alpha (LT-α) are immunomodulators that have been hypothesized to contribute to susceptibility to type 1 diabetes (T1D). Several polymorphisms in the TNF and LT-α loci have been extensively studied for T1D association, with conflicting reports. In this study, we examined two TNF variants and one LT-α variant for T1D association in 283 Caucasian, multiplex T1D families for which complete human leukocyte antigen (HLA) genotyping data are available. Initially, association with T1D was seen for LT-α A1069G (intron A, p = 0.011, rs909253) and TNF G(−308)A (p < 1 × 10⁻⁵, rs1800629), but no association was observed for TNF G(−238)A (rs361525). After adjusting the data for linkage disequilibrium (LD) with DRB1-DQB1 haplotypes, however, only one polymorphism, TNF G(−238)A showed significant association with T1D (p < 0.006). When HLA-DR3 haplotypes were examined, the A allele of TNF G(−238)A was significantly overtransmitted to affected offspring (p < 0.009). Including HLA-B data in the analysis revealed that TNF (−238)A is present exclusively on DR3 haplotypes that also carry HLA-B18. Transmission proportion of B18-DR3 haplotypes did not differ between those with TNF (−238)A and those with TNF (−238)G. Thus, variation at TNF does not affect the T1D risk for B18-DR3 haplotypes, and the apparent association of TNF(−238)A with T1D may simply reflect its presence on a high-risk haplotype.     

High endemicity of human T-cell lymphotropic virus type 1 among pregnant women in peru

Human T-cell lymphotropic virus type 1(HTLV-1) is associated with adult T-cell leukemia, tropical spastic paraparesis, and other immune-mediated diseases. There are reports of groups with high prevalences of HTLV-1 infection in Peru, but there is limited knowledge of the epidemiology of infection or which routes of infection are most important. We studied 2,492 women presenting to a large maternity hospital in Lima for prenatal, delivery, or abortion services. HTLV-1 seropositivity was confirmed in 42 women (1.7%; 95% confidence interval, 1.2-2.2). Seroprevalence increased with age but did not vary by region of birth or recency of migration to Lima. Age greater than 30 years and sexual intercourse before 20 years of age were strongly and independently associated with infection. History of abortion and history of transfusion were of borderline significance. Women whose male partner had a characteristic that might be a marker for risk of sexually transmitted infections were also more likely to be infected. HTLV-1 is common among Peruvians throughout the country and is maintained by a low level of neonatally acquired infection that is amplified by sexual transmission. In addition to screening of the blood supply, instituted in 1997, programs designed to reduce neonatal and sexual transmission should be effective.     

Evaluation of a solid-phase immunoassay for the simultaneous detection of antibodies to human immunodeficiency virus type 1 and human T-cell lymphotropic virus type I.

We describe the evaluation of a solid-phase immunoassay developed for the simultaneous detection of antibodies to human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus types I (HTLV-I) and II (HTLV-II) in human serum. The immunoassay employs a mixture of HIV-1 and HTLV-I whole viral lysates immobilized in the wells of microtiter plates. Evaluation of genetically well-pedigreed specimens along with normal blood donor samples indicated that the performance characteristics of the test were equivalent to the sensitivity and specificity of individual tests licensed by the Food and Drug Administration for antibodies to HIV-1 and HTLV-I. Furthermore, the test was also able to detect the presence of cross-reacting antibodies in HTLV-II-infected individuals. The use of such a test would greatly reduce the continually mounting costs associated with screening transfusable products for infectious agents.