Human T-cell Lymphotropic Virus Type 1 Carriers Research Articles

A C77G point mutation in CD45 exon 4, which is associated with the development of multiple sclerosis and increased susceptibility to HIV-1 infection, is undetectable in Japanese population.

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of Human T-cell lymphotropic virus type 1 (HTLV-1) infection. It remains unknown why the majority of infected people remain healthy whereas only approximately 2-3% develop disease. Recently, heterozygous state of CD45 exon 4 mutation (C77C wild type and C77G mutant) was reported to be associated with development of multiple sclerosis in German patients and increased susceptibility to HIV-1 infection in the United Kingdom. To investigate whether this mutation is associated with the development of HAM/TSP, we studied a group of 164 HAM/TSP patients and 108 asymptomatic HTLV-1 carriers in Kagoshima (HTLV-1 endemic area in Southern Japan) by using PCR-RFLP and subsequent direct sequencing analysis. All 272 subjects showed homozygosity in the CD45 exon 4, suggesting that this mutation is absent or very rare in Japanese population.

Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8+ T cells, and disease severity in HTLV-1–associated myelopathy (HAM/TSP)

To investigate the role of viral expression in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1), a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) of HTLV-1 tax messenger RNA (mRNA) using ABI Prism 7700 Sequence Detection System was developed. Using this system, the HTLV-1 tax mRNA load was compared with HTLV-1 proviral DNA load, HTLV-1 Tax protein expression, HTLV-1 Tax-specific CD8(+) T-cell frequency, and disease severity of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This approach was a sensitive and specific technique for the precise quantification of HTLV-1 tax mRNA. The total amount of HTLV-1 tax mRNA and mRNA expression level in HTLV-1-infected cells (mRNA/DNA ratio) were higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The HTLV-1 tax mRNA load correlated with the HTLV-1 proviral DNA load ex vivo, the Tax protein expression in vitro, and the Tax-specific CD8(+) T-cell frequency ex vivo. The HTLV-1 tax mRNA load also correlated with disease severity in HAM/TSP patients. These data suggest that increased HTLV-1 expression plays an important role in the pathogenesis of HAM/TSP, and the HTLV-1 tax mRNA level could be a useful predictor of disease progression in patients with HAM/TSP.

Elevated Levels of Soluble Adhesion Molecules in Sera and BAL Fluid of Individuals Infected With Human T-Cell Lymphotropic Virus Type 1

T-lymphocytic alveolitis and increased levels of interleukin-2 receptor-alpha (CD25)-bearing T cells in the BAL fluid (BALF) of human T-cell lymphotropic virus type 1 (HTLV-1) carriers have been reported. Several chemokines and adhesion molecules may contribute to the accumulation of T lymphocytes in the lungs of HTLV-1 carriers. To clarify the correlation between adhesion molecules and HTLV-1-associated pulmonary disorders, we compared the distribution of T-lymphocyte subsets and soluble adhesion molecules, including soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble L-selectin (sL-selectin), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin), in BALF and peripheral blood, between HTLV-1 carriers and noninfected healthy subjects. Flow cytometric analysis with monoclonal antibodies to cell-surface antigens was used to identify T-lymphocyte subsets in BALF samples from HTLV-1 carriers (n = 13) and noninfected healthy control subjects (n = 10). The levels of various soluble adhesion molecules in serum and in BALF were estimated by enzyme-linked immunosorbent assay. Higher percentages of CD3+ cells, CD3-expressing human leukocyte antigen-DR antigen, and CD3+CD25+ cells were detected in the BALF of HTLV-1 carriers than in that of noninfected control subjects. The concentrations of sICAM-1, sVCAM-1, sL-selectin, SE- selectin, and sP-selectin in the sera of patients were significantly higher than those in noninfected healthy control subjects. The concentration of sICAM-1 in the BALF of patients was significantly higher than that in noninfected healthy control subjects, and the concentration of sICAM-1 correlated well with the percentage of CD3+CD25+ cells. The concentrations of adhesion molecules in the sera of and sICAM-1 in the BALF of HTLV-1 carriers were significantly higher than those in noninfected individuals, and the concentration of sICAM-1 correlated well with the percentage of CD3+CD25+ cells in BALF. Our results suggest a possible interaction between activated T cells bearing CD25 and soluble adhesion molecules, especially sICAM-1, which may contribute to the pulmonary involvement in HTLV-1 carriers.

Human T-lymphotropic virus type 1 infection

Human T-cell lymphotropic virus type-1 (HTLV-1) is aetiologically associated with adult T-cell leukaemia/lymphoma (ATL). HTLV-1 infection can also lead to various non-malignant diseases, for example, HTLV-1 associated myelopathy/tropical spastic paraparesis and HTLV-1 uveitis. HTLV-1 is endemic in southern Japan and the Caribbean. HTLV-1 infection is mainly transmitted by either breast-feeding, sexual intercourse or blood transfusions. Primary prevention of HTLV-1 in endemic areas by screening of blood and by refraining from breast-feeding have been successful. The incidence of ATL is rather low among HTLV-1 carriers (<5%). The precise mechanism of development of ATL remains unknown. It is a multiple-step process which does not require viral expression in the later stages of leukaemogenesis. Many samples have mutations of the tumour suppressor genes, p53 and/or p16INK4A. Four subtypes of ATL have been identified, each having distinctive clinical features. Monoclonal integration of HTLV-1 proviral DNA into tumour cells is found in each of the subtypes. At present, no effective therapy for ATL exists.

Human T-cell lymphotropic virus type 1 infection and ocular manifestations in São Paulo, Brazil.

Although human T-cell lymphotropic virus type 1 (HTLV-1)-associated uveitis has been well recognized in Japan, related studies in Brazil are scarce. We performed a serologic survey for HTLV-1 infection among patients with uveitis and investigated the ocular findings in HTLV-1-asymptomatic carriers. One hundred ninety serum samples from patients with uveitis of determined (n = 137) and undetermined origins (n = 53) being examined at the Uveitis Service, University of São Paulo, São Paulo, Brazil, underwent testing using HTLV enzyme-linked immunosorbent assay and discriminatory Western blots. One hundred five asymptomatic blood donors and/or their relatives who were seropositive for HTLV-1 (carrier group) and 105 age- and sex-paired blood donors who were seronegative for HTLV-1 (control group) underwent ocular evaluation. For the statistical analysis, chi2 test was used. Only 1 patient with uveitis was seropositive for HTLV- 1, and she belonged to the group with uveitis of undetermined origin. Results of tear films were evaluated in 52 carriers. The prevalence of a decreased tear break-up time was significantly higher in the carrier compared with the control group (P = .02). Two carriers had keratoconjunctivitis sicca. Three of the 105 carriers exhibited mild uveitis (cells in the vitreous, retinal and choroidal infiltrates, retinal vasculitis, and bilateral pars planitis). Retinal pigmentary changes were found in both groups (no statistical difference). Early tear abnormalities may be present in asymptomatic carriers, and mild uveitis may be found among them. The relatively low seroprevalence of HTLV-1 in the Brazilian population made it difficult to establish the real importance of HTLV-1-associated uveitis among our patients with uveitis.

Correlation between human T cell lymphotropic virus type-1 and Strongyloides stercoralis infections and serum immunoglobulin E responses in residents of Okinawa, Japan.

To clarify the relationship between Strongyloides stercoralis, infection with human T cell lymphotropic virus type-1 (HTLV-1), and serum immunoglobulin E (IgE) levels, epidemiologic investigations of these two infections were conducted in inhabitants of Okinawa, a subtropical zone in Japan. Blood and feces samples were taken from 1,347 healthy inhabitants (554 males and 793 females). Antibody to HTLV-1 was measured by particle agglutination, enzyme-linked immunosorbent assay, and Western blotting. The presence of Strongyloides was determined by direct detection of rhabditiform larvae in fresh stool on agar-plate cultures. Serum IgE levels in 127 inhabitants were measured by a fluoroenzyme immunoassay. Antibody to HTLV-1 was detected in 23.0% of the blood samples and was more frequent in females (25.1%) than in males (20.0%) (P < 0.05). Strongyloides were detected in 21.9% of the feces samples and were more frequent in males (31.9%) than in females (14.9%) (P < 0.001). The prevalence of both infections increased with age, especially in persons 50 years of age and older: The prevalence of Strongyloides infection was significantly higher in HTLV-1 carriers (31.6%) than in those without HTLV-1 infection (P < 0.001). The level of IgE was low in HTLV-1 carriers, and significantly lower in HTLV-1 carriers than in noncarriers among inhabitants with Strongyloides infection. Both HTLV-1 and Strongyloides infections are endemic in the area studied.

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.

Detection of human T-cell lymphotropic virus type 1 infection by the polymerase chain reaction using dried blood specimens on filter papers

A simple method for detection of proviral DNA sequences of human T-cell lymphotropic virus type 1 (HTLV-1) was developed using dried blood specimens on filter papers. The whole blood was blotted onto the Guthrie paper. After the blood has dried, the blotted paper was punched out into small discs. The discs were then boiled to prepare the template for PCR (filter paper-PCR method). The filter paper-PCR method detected even a single HTLV-1-infected cell in three discs. The sensitivity of the filter paper-PCR method was equivalent to that of the method in which DNA was extracted with phenol and used as the template for PCR (DNA extraction-PCR method). In addition, DNA in the blotted filter paper was still utilizable as the template after the storage at 25°C for at least 7 wk. A total of 53 clinical specimens from 30 seropositive and 23 seronegative individuals who were screened by particle agglutination (PA) test were analysed for HTLV-1 DNA by both PCR methods. Of 30 PA-positive specimens, 28 were also positive for HTLV-1 antibody by Western blot (WB) analysis, but two were indeterminate. The twenty eight WB-positive and one of the two indeterminate specimens were positive for HTLV-1 proviral DNA by both PCR methods. Of 23 PA-negative specimens, 22 were negative for HTLV-1 proviral DNA by both PCR methods. However, one PA-negative specimen was positive by both PCR methods. This patient was a 16-mth-old infant who was born to an HTLV-1 carrier mother and fed thereafter without her breast milk. In comparison to DNA extraction-PCR method, the sensitivity and specificity of the filter paper-PCR method was 100%, respectively.