Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection.

Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed to disease-associated immune suppression. ATL cells have a CD4+CCR4+CD26-CD7- immunophenotype but infected cells with this immunophenotype ('ATL-like' cells) are also present in non-malignant HTLV-1 infection. We hypothesized that 'ATL-like' and ATL cells have distinct cytokine producing capacity and a switch in the cytokines produced occurs during leukemogenesis. Seventeen asymptomatic carriers (ACs), 28 patients with HTLV-1-associated myelopathy (HAM) and 28 with ATL were studied. Plasma IL-10 concentration and the absolute frequency of IL-10-producing CD4+ T cells were significantly higher in patients with ATL compared to AC. IL-10-producing ATL cells were significantly more frequent than 'ATL-like' cells. The cytokine-producing cells were only a small fraction of ATL cells. Clonality analysis revealed that even in patients with ATL the ATL cells were composed not only of a single dominant clone (putative ATL cells) but also tens of non-dominant infected clones ('ATL-like' cells). The frequency of cytokine-producing cells showed a strong inverse correlation with the relative abundance of the largest clone in ATL cells suggesting that the putative ATL cells were cytokine non-producing and that the 'ATL-like' cells were the primary cytokine producers. These findings were confirmed by RNAseq with cytokine mRNA expression in ATL cells in patients with ATL (confirmed to be composed of both putative ATL and 'ATL-like' cells by TCR analysis) significantly lower compared to 'ATL-like' cells in patients with non-malignant HTLV-1 infection (confirmed to be composed of hundreds of non-dominant clones by TCR analysis). A significant inverse correlation between the relative abundance of the largest clone and cytokine mRNA expression was also confirmed. Finally, 'ATL-like' cells produced less pro- and more anti-inflammatory cytokines than non 'ATL-like' CD4+ cells (which are predominantly HTLV uninfected). In summary, HTLV-1 infection of CD4+ T cells is associated with a change in cytokine producing capacity and dominant malignant clonal growth is associated with loss of cytokine producing capacity. Non-dominant clones with 'ATL-like' cells contribute to plasma cytokine profile in patients with non-malignant HTLV-1 infection and are also present in patient with ATL.

Hypometabolism of watershed areas of the brain in HTLV-1-associated myelopathy/tropical spastic paraparesis.

In previous studies of human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), areas of slow blood flow in the spinal cord were related to pathological changes. While the pathological changes in the brain are milder than those in the spinal cord, they are also more significant in sites with slow blood flow. In this study, we investigated brain glucose metabolism in slow blood flow areas using fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). Clinical features and brain (18)F-FDG-PET parameters were analyzed in six patients with HAM/TSP. For comparison of PET data, eight healthy volunteers were enrolled as normal controls (NLs). Glucose metabolism in the watershed areas of the middle and posterior cerebral arteries, as compared with that in the occipital lobes as a control, was significantly lower in HAM/TSP patients than in NLs. This result confirmed the relationship between slow blood flow areas and hypometabolism in HAM/TSP, and is consistent with previous findings that pathological changes are accentuated in sites with slow blood flow.

Systems biology approaches reveal a specific interferon-inducible signature in HTLV-1 associated myelopathy.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.

HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP.

BACKGROUND: HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation. METHODS: We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified 'strong' HBZ binders; the remainder were classified 'weak binders'. RESULTS: The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders. CONCLUSION: Clonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic.

The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein.

Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.

Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.

Molecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The αß TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD-HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide-MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.

HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1).

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1--SOCS1--was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/ß and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-ß production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.

Depletion of dendritic cells enhances susceptibility to cell-free infection of human T cell leukemia virus type 1 in CD11c-diphtheria toxin receptor transgenic mice.

Human T cell leukemia virus type 1 (HTLV-1) is associated with two immunologically distinct diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia. The genesis of these diseases is believed to be associated with the route (mucosa versus blood) and mode (cell-free versus cell-associated) of primary infection as well as the modulation of dendritic cell (DC) functions. To explore the role of DCs during early HTLV-1 infection in vivo, we used a chimeric HTLV-1 with a replaced envelope gene from Moloney murine leukemia virus to allow HTLV-1 to fuse with murine cells, which are generally not susceptible to infection with human retroviruses. We also used a CD11c-diphtheria toxin receptor transgenic mouse model system that permits conditional transient depletion of CD11c(+) DCs. We infected these transgenic mice with HTLV-1 using both cell-free and cell-associated infection routes in the absence and presence of DCs. The ablation of DCs led to an enhanced susceptibility to infection with cell-free but not cell-associated HTLV-1 in both CD4 and non-CD4 fractions, as measured by the proviral load. Infection with cell-free virus in the absence of DCs was also found to have increased levels of Tax mRNA in the non-CD4 fraction. Moreover, depletion of DCs significantly dampened the cellular immune response (IFN-gamma(+)CD8(+) T cells) against both cell-free and cell-associated virus. These results uniquely differentiate the involvement of DCs in early cell-free versus late cell-associated infection of HTLV-1 and highlight a significant aspect of viral immunopathogenesis related to the progression of adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis after the initial infection.

Upregulation of hsa-miR-125b in HTLV-1 asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis patients.

The retrovirus human T lymphotropic virus type 1 (HTLV-1) promotes spastic paraparesis, adult T cell leukaemia and other diseases. Recently, some human microRNAs (miRNAs) have been described as important factors in host-virus interactions. This study compared miRNA expression in control individuals, asymptomatic HTLV-1 carriers and HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis patients. The proviral load and Tax protein expression were measured in order to characterize the patients. hsa-miR-125b expression was significantly higher in patients than in controls (p = 0.0285) or in the HAM group (p = 0.0312). Therefore, our findings suggest that miR-125b expression can be used to elucidate the mechanisms of viral replication and pathogenic processes.

High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease.

HTLV-I-specific CD8(+) T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8(+) T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8(+) T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-gamma production in CD8(+) T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8(+) T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-gamma production in CD8(+) T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8(+) T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.

Dysregulation of TGF-beta signaling and regulatory and effector T-cell function in virus-induced neuroinflammatory disease.

We previously demonstrated that CD4(+)CD25(+) T regulatory cells (Tregs), important for the maintenance of immune tolerance and prevention of autoimmune disease, from patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) exhibit reduced Foxp3 expression and Treg suppressor function compared with healthy donors. Since TGF-beta signaling has been previously reported to be critical for both Foxp3 expression and Treg function, we examined whether this signaling pathway was dysregulated in patients with HAM/TSP. Levels of TGF-beta receptor II (TGF-betaRII) as well as Smad7 (a TGF-beta-inducible gene) were significantly reduced in CD4(+) T cells in patients with HAM/TSP compared with healthy donors, and the expression of TGF-betaRII inversely correlated with the HTLV-I tax proviral load. Importantly, both CD4(+)CD25(+) and CD4(+)CD25(-) T cells from HAM/TSP patients exhibited reduced TGF-betaRII expression compared with healthy donors, which was associated with functional deficits in vitro, including a block in TGF-beta-inducible Foxp3 expression that inversely correlated with the HTLV-I tax proviral load, loss of Treg suppressor function, and escape of effector T cells from Treg-mediated control. This evidence suggests that a virus-induced breakdown of immune tolerance affecting both regulatory and effector T cells contributes to the pathogenesis of HAM/TSP.

Childhood-onset HAM/TSP with progressive cognitive impairment.

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy, usually with adult-onset. Very few cases of childhood-onset have been described, most presenting with progressive paraparesis and sphincteric disturbances as in the adult form. Here we report a young male with childhood-onset of HAM/TSP and progressive cognitive and behavioral disturbances. A serological screening revealed HTLV-I infection, confirmed by Western Immunoblotting analysis. Molecular characterization of amplified HTLV-I proviral DNA has been performed both in the patient and his mother by LTR sequence analysis, and HLA genotype inheritance was evaluated. Our case indicates the possibility that cognitive dysfunctions may be one manifestation of HTLV-I infection in childhood.

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.

Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease.

CD4(+)CD25(+) Tregs are important in the maintenance of immunological self tolerance and in the prevention of autoimmune diseases. As the CD4(+)CD25(+) T cell population in patients with human T cell lymphotropic virus type I-associated (HTLV-I-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) has been shown to be a major reservoir for this virus, it was of interest to determine whether the frequency and function of CD4(+)CD25(+) Tregs in HAM/TSP patients might be affected. In these cells, both mRNA and protein expression of the forkhead transcription factor Foxp3, a specific marker of Tregs, were lower than those in CD4(+)CD25(+) T cells from healthy individuals. The virus-encoded transactivating HTLV-I tax gene was demonstrated to have a direct inhibitory effect on Foxp3 expression and function of CD4(+)CD25(+) T cells. This is the first report to our knowledge demonstrating the role of a specific viral gene product (HTLV-I Tax) on the expression of genes associated with Tregs (in particular, foxp3) resulting in inhibition of Treg function. These results suggest that direct human retroviral infection of CD4(+)CD25(+) T cells may be associated with the pathogenesis of HTLV-I-associated neurologic disease.

Reduced Foxp3 expression with increased cytomegalovirus-specific CTL in HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients show high immune responses to HTLV-I. However, it is unclear whether the cytotoxic T lymphocyte (CTL) responses to other chronic viruses also increase. We investigated the responses in the peripheral blood by using HLA-A*0201/peptide pentamers. The frequency of cytomegalovirus (CMV)-specific CTL tended to be higher in HAM/TSP patients than in healthy controls (HCs). The frequency of CMV-specific CTL positively correlated with that of HTLV-I Tax-specific CTL. The frequency of Foxp3+ cells in CD4+ lymphocytes tended to be higher in HAM/TSP patients than in ACs and HCs. The expression level of Foxp3 was lower in HAM/TSP patients than in HCs and was inversely correlated with the CMV-specific CTL frequency. A percentage of Foxp3+ cells showed a positive correlation with the HTLV-I proviral load. These results suggest that a decrease in the Foxp3 expression may contribute to the high immune response to CMV and that the Foxp3+ regulatory T cells may play a role in the immune surveillance of HTLV-I.

Increased frequency of CD4+T cells expressing fractalkine receptor CX3CR1 in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), but its AIDS susceptible polymorphisms are not associated with the disease.

To investigate whether fractalkine receptor CX3CR1 polymorphisms that have been associated with rapid progression to AIDS among HIV-1 positive individuals also affects the risk of human T cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), we compared the allele frequencies of V249I and T280M between 233 HAM/TSP patients and 213 HTLV-1 seropositive asymptomatic carriers (HCs). Although the frequency and absolute number of peripheral blood CX3CR1+CD4+T cells were significantly increased in HAM/TSP patients compared to HCs and uninfected controls independent of HTLV-1 trans-activator protein Tax, we could not observe any association between the two polymorphisms and the risk of HAM/TSP in our cohort.

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.

Role of Integrin Signaling Activation on the Development of Human T Cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis: Its Relationship to HTLV-1-Infected CD4+ T Cell Transmigrating Activity into the Tissues.

The main clinical feature of human T cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is slowly progressive spastic paraparesis with bladder dysfunction. HAM/TSP is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by the interaction between infiltrated Th1-like, HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells (CTL), is probably critical for the induction of chronic inflammation. Although the HTLV-1-infected CD4+ T cells in HAM/TSP appear to play a crucial role in the initial pathogenesis of HAM/TSP, the exact mechanisms of how these cells acquire their function as the first responders in the pathogenesis of HAM/TSP still remain unresolved. Herein, we propose the importance of the activation of both outside-in signals from integrin signaling and inside-out signals for integrin signaling in the HTLV-1-infected CD4+ T cells of HAM/TSP patients.

High production of RANTES and MIP-1alpha in the tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM).

Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with progressive neurological disorders and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). The pathogenesis of TSP/HAM is considered as immune mediated, involving cytotoxic T cell (CTL) responses to a number of viral proteins and notably the regulation protein Tax. T CD8+ cells produce beta-chemokines, which are important in the anti-viral response. In the present study, we have analyzed the CC chemokines (RANTES, MIP-1beta and MIP-1alpha) production in retrovirus-infected subjects. A total of 191 subjects were studied: 52 healthy controls, 72 asymptomatic HTLV-1-infected carriers and 67 TSP/HAM patients. Peripheral blood mononuclear cells were maintained in the presence or absence of PHA, and supernatant fluids were assayed using EIA. MIP-1beta concentration was not significantly different across groups, but RANTES and MIP-1alpha concentrations showed significant differences when the three groups were compared. In TSP/HAM patients, the increase in the production of chemokines may lead to a recruitment of pro-inflammatory factors, contributing to the membrane's myelin damage.