Immunogenetics and the Pathological Mechanisms of Human T-Cell Leukemia VirusType 1- (HTLV-1-)Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)

Human T-cell leukemia virus type 1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence suggests that complex virus-host interactions play an important role in determining the risk of HAM/TSP. This review focuses on the role of the immune response in controlling or limiting viral persistence in HAM/TSP patients, and the reason why some HTLV-1-infected people develop HAM/TSP whereas the majority remains asymptomatic carriers of the virus

Association Between HTLV-1 Genotypes and Risk of HAM/TSP

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder presenting with spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities, which develops in a small minority of HTLV-1-infected individuals. HTLV-1-specific T cells are efficiently activated through dedicated human leukocyte antigen-mediated mechanisms, a process considered deeply involved with its pathogenesis. It has been reported that the lifetime risk of developing HAM/TSP differs between ethnic groups, and there is an association between HTLV-1 tax gene subgroups (i.e., tax subgroup-A or -B), which correspond to HTLV-1 “cosmopolitan subtype 1a subgroup A (i.e., transcontinental subgroup)” and “cosmopolitan subtype 1a subgroup B (i.e., Japanese subgroup),” respectively, and the risk of HAM/TSP in the Japanese population. These findings suggest that a given host’s susceptibility to HAM/TSP is deeply connected with both differences in genetically determined components of the host immune response and HTLV-1 subgroup. Therefore, it is crucial for ongoing work to focus on developing novel treatments and preventative approaches for HAM/TSP. In this review, based on an overview of the topic and our latest research findings, the role of the HTLV-1 subgroup on the effects of virus–host interactions in the pathogenesis of HAM/TSP is discussed

In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP)

<p>Abstract</p> <p>Background</p> <p>Recently, human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL) development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases.</p> <p>Results</p> <p>We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs) and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV-1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1-infected cell was decreased after successful immunomodulatory treatment for HAM/TSP.</p> <p>Conclusion</p> <p>These findings suggest that <it>in vivo </it>expression of HBZ plays a role in HAM/TSP pathogenesis.</p

EOS, an Ikaros family zinc finger transcription factor, interacts with the HTLV-1 oncoprotein Tax and is downregulated in peripheral blood mononuclear cells of HTLV-1-infected individuals, irrespective of clinical statuses

Background: EOS plays an important role in maintaining the suppressive function of regulatory T cells (Tregs), and induces a regulated transformation of Tregs into T helper-like cells, which are capable of secreting proinflammatory cytokines in response to specific inflammatory signals. Meanwhile, significant reduction in Treg activity along with production of proinflammatory cytokines has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Methods: In this study, to examine whether there is an alteration in EOS expression in peripheral blood mononuclear cells (PBMCs) derived from HTLV-1-infected individuals especially HAM/TSP, we investigated the expression of HTLV-1 tax genotype, proviral load (PVL), and the mRNA expression of tax, HBZ and EOS in HTLV-1 infected individuals including adult T-cell leukemia/lymphoma (ATL), HAM/TSP, or asymptomatic carriers. The expression levels of EOS mRNA and protein in various HTLV-1-infected or uninfected human T-cell lines were also investigated. Results: EOS was highly expressed at the protein level in most HTLV-1 infected T-cell lines, and was augmented after the HTLV-1 regulatory factor Tax was induced in a Tax-inducible JPX-9 cell line. Immunoprecipitation experiments demonstrated a physical interaction between EOS and the viral regulatory protein Tax, but not HBZ. Meanwhile, there was a significant decrease in EOS mRNA levels in PBMCs of HTLV-1 infected individuals irrespective of their clinical statuses. We found an inverse correlation between EOS mRNA levels and HTLV-1 PVL in ATL patients, and positive correlations between both EOS mRNA load and PVL, and EOS and HBZ mRNA load in HAM/TSP patients, whereas this correlation was not observed in other clinical statuses. Conclusions: These findings suggest that both Tax and HBZ can alter the expression of EOS through undetermined mechanisms, and dysregulated expression of EOS in PBMCs of HTLV-1 infected individuals may contribute to the pathological progression of HTLV-1-associated diseases, such as ATL and HAM/TSP