Impact of HIV co-infection on immunological biomarker profile of HTLV-1 infected patients.

The impact of HIV co-infection on the plasma immunological biomarker profile of HTLV-1 infected patients was evaluated. The plasma levels of leukotrienes and chemokines/cytokines were quantified by ELISA and Cytometric Bead Array. A total of 138 volunteers were enrolled and divided into two subgroups ("HTLV-1(+)HIV(-)" and "HTLV-1(+)(HIV(+)"), which were categorized according to the HTLV-1-associated neurological disease (AS, pHAM and HAM). Reference controls were BD and HIV mono-infected patients. HAM(+) exhibited higher CD4+ T-cell counts as compared to HIV+ mono-infected patients and lower HTLV-1 proviral load as compared to mono-infected HAM(-) patients. AS(+) exhibited higher levels of CysLT, CXCL8/IL-8 and lower levels of CCL5/RANTES as compared to AS(-). Increased levels of IL-6 and TNF with reduced levels of CXCL10/IP10 and CCL5/RANTES were observed in co-infected pHAM(+) as compared to mono-infected pHAM(-). HAM(+) patients revealed an increase in CXCL8/IL-8, CCL2/MCP-1, CXCL-10/IP-10, TNF and a decrease in IL-2 as compared to HAM(-) subgroup.

Morphological alterations in minor salivary glands of HTLV1+ patients: A pilot study.

BACKGROUND: Among the complex of HTLV-associated diseases, Sjögren's syndrome (SS) is one of the most controversial. This work aims to detect morphological and inflammatory alterations, including clues of the presence of HTLV-1, in minor salivary glands of patients with dryness symptoms. METHODS: We have assessed HTLV-1-seropositive patients (HTLV-1 group) and patients with SS (SS group). We used formalin-fixed, paraffin-embedded minor salivary gland tissue to evaluate the morphological aspects and, by means of immunohistochemistry, the presence of Tax protein, CD4, CD8 and CD20 cells. Additionally, viral particles and proviral load were analysed by PCR. RESULTS: The HTLV-1 group had the highest prevalence of non-specific chronic sialadenitis (85.71%; P = 0.017) and greater amount of T CD8+ cells. In the SS group, focal lymphocytic sialadenitis (80%; P = 0.017) prevailed, with a greater amount of B CD20+ . Both immunohistochemistry and PCR identified the Tax protein and its gene in the salivary glands of both groups and in similar proportions. CONCLUSION: The results indicate that HTLV-1-seropositive patients have different patterns of morphological/inflammatory alterations, suggesting a likely difference in the process of immune activation.

Protein Profile of Blood Monocytes is Altered in HTLV-1 Infected Patients: Implications for HAM/TSP Disease.

Human T-cell lymphotropic virus type-1 (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The endothelial breakdown and migration of leukocytes, including monocytes, to the spinal cord are involved in HAM/TSP development. Monocytes from HTLV-1-infected individuals exhibit important functional differences when compared to cells from uninfected donors. Using proteomic shot gun strategy, performed by nanoACQUITY-UPLC system, we analyzed monocytes isolated from peripheral blood of asymptomatic carriers (AC), HAM/TSP and uninfected individuals. 534 proteins were identified among which 376 were quantified by ExpressionE software. Our study revealed a panel of changes in protein expression linked to HTLV-1 infection. Upregulation of heat shock proteins and downregulation of canonical histone expression were observed in monocytes from HTLV-1-infected patients. Moreover, expression of cytoskeleton proteins was increased in monocytes from HTLV-1-infected patients, mainly in those from HAM/TSP, which was confirmed by flow cytometry and fluorescence microscopy. Importantly, functional assays demonstrated that monocytes from HAM/TSP patients present higher ability for adhesion and transmigration thought endothelium than those from AC and uninfected individuals. The major changes on monocyte protein profile were detected in HAM/TSP patients, suggesting that these alterations exert a relevant role in the establishment of HAM/TSP.

Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals

Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.

Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals.

Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.

The elevated interferon gamma production is an important immunological marker in HAM/TSP pathogenesis.

Human T-lymphotropic virus type 1 (HTLV-1) is the agent of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may occur in >5% of patients during their lifetime. HTLV-1-infection causes disturbances in the immune system, and the viral load may also play an important role in the pathogenesis of HAM/TSP. Some cytokines are involved in the pathogenesis of this disorder. We have determined IL-2, IL-4, IL-10, IL-12 p70, IFN-gamma and TNF-alpha production among HTLV-1-infected subjects from our HTLV-out Clinic in Institute of Infectious 'Emílio Ribas' in Sao Paulo city, Brazil. PBMC obtained from healthy controls (n = 32), asymptomatic HTLV-1 carriers (n = 68) and HAM/TSP patients (n = 44) were grown in the absence and in the presence of phytohaemagglutinin (PHA), and the supernatants' fluids were measured for cytokines production. IL-2 levels were increased in the asymptomatic HTLV-1 carriers, and IFN-gamma was increased in both groups of patients (asymptomatic HTLV-1 carriers and more significantly among HAM/TSP patients). IL-4, IL-10, TNF-alpha and IL-12 p70 levels were not significantly increased on both groups of patients, as compared with controls. The major finding of this study is that IFN-gamma was an important cytokine for the HAM/TSP pathogenesis. Therefore, immune modulation of IFN-gamma may be critical to treat of HAM/TSP patients.

HTLV-I alters the multidrug resistance associated protein 1 (ABCC1/MRP1) expression and activity in human T cells.

The human T cell lymphotropic/leukaemia virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The multidrug resistance associated protein 1 (ABCC1) plays multiple functions in physiopathologic responses. The expression and activity of ABCC1 was studied in T lymphocytes from uninfected and HTLV-I-infected individuals (both asymptomatic and symptomatic/HAM/TSP). ABCC1 expression and activity was reduced to nearly half in T lymphocytes from infected patients compared to control lymphocytes. Only 51.6% of CD4(+) cells from HAM/TSP patients expressed ABCC1 whereas this was seen in 60.3% from asymptomatic individuals, compared to an expression of around 86% in controls. Our results suggest that ABCC1 is negatively regulated in HTVL-I infection, supplying a novel target to investigate the pathogenesis of HTLV-I.

Human T-lymphotropic virus type II and neurological disease.

Human T-lymphotropic virus type I (HTLV-I) and type II (HTLV-II) are closely related retroviruses with similar biological properties and common modes of transmission. HTLV-I infection is endemic in well-defined geographic regions, and it is estimated that some 20 million individuals are infected worldwide. Although most infected individuals are asymptomatic carriers, some 2 to 5% will develop a chronic encephalomyelopathy, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast with HTLV-I, the role of HTLV-II in the development of neurological disorders is much less clear. HTLV-II is endemic in many native Amerindian groups and epidemic in injecting drug users (IDUs) worldwide. To evaluate the role of HTLV-II in neurological disease, we have critically reviewed all reported cases of HTLV-II-associated disorders. This has confirmed that although rare infection is associated with a disorder clinically similar or identical to HAM/TSP. However, most reports that have attributed infection to a range of other neurological disorders are difficult to evaluate in that in many cases either the association appears to be fortuitous or the presentations were confounded by a background of concomitant human immunodeficiency virus-1 infection and/or active IDU. In view of the many HTLV-II-infected individuals in urban areas of North America and Europe, neurologists should be aware of the potential clinical consequences of this infection.

Decreased GATA3 mRNA expression in human T-cell lymphotropic virus type 1 (HTLV-1) infection.

GATA3 is a specific T-cell transcription factor involved in the expression of T-cell receptor (TCR). In order to characterize the relationship between HTLV-1 infection, which has been reported to be associated with down-regulation of genes belonging to the TCR/CD3 complex, and the transcription factor GATA3, we evaluated, by semi-quantitative RT-PCR, the expression of GATA3 gene in HTLV-1 carriers and individuals with related diseases. The study included 4 asymptomatic carriers, 2 patients with adult T-cell leukaemia/lymphoma (ATLL), 1 patient with HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 7 healthy blood donors. A considerable decrease in the expression of the GATA3 mRNA was observed in all subjects infected by HTLV-1 and no expression of GATA3 mRNA was observed in 1 subject with ATLL and in 1 with HAM/TSP.

Infección por HTLV-I, leucemia de células T del adulto y factor con actividad de parathormona

La infección por el virus linfotrópico humano tipo I (HTLV-I) se ha asociado a la paraparesia espástica tropical (PET) y a la leucemia/linfoma de células T del adulto (ATL). Recientemete se demostró que los desordenes del metabolismo del calcio que acompañan la ATL son debidos a la secreción de un factor con actividad de parthormonas producido por los linfocitos infectados por el HTVL-I. Se presenta el caso de una paciente con anticuerpos contra el HTVL-I, anormalidades en el metabolismo del calcio y con parámetros que la clasifican en uno de los subtipos de ATL.