Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4⁺ T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4⁺ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4⁺CD25⁺CCR4⁺ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4⁺CD25⁺CCR4⁺ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ⁺ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease.

Human T-cell leukemia virus type-1 (HTLV-1) causes two distinct diseases, adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since there are no disease-specific differences among HTLV-1 strains, the etiological mechanisms separating these respective lymphoproliferative and inflammatory diseases are not well understood. In this study, by using IL-2-dependent HTLV-1-infected T-cell lines (ILTs) established from patients with ATL and HAM/TSP, we demonstrate that the anti-inflammatory cytokine IL-10 and its downstream signals potentially act as a switch for proliferation in HTLV-1-infected cells. Among six ILTs used, ILTs derived from all three ATL patients grew much faster than those from three HAM/TSP patients. Although most of the ILTs tested produced IFN-γ and IL-6, the production of IL-10 was preferentially observed in the rapid-growing ILTs. Interestingly, treatment with exogenous IL-10 markedly enhanced proliferation of the slow-growing HAM/TSP-derived ILTs. The IL-10-mediated proliferation of these ILTs was associated with phosphorylation of STAT3 and induction of survivin and IRF4, all of which are characteristics of ATL cells. Knockdown of STAT3 reduced expression of IL-10, implying a positive-feedback regulation between STAT3 and IL-10. STAT3 knockdown also reduced survivin and IRF4 in the IL-10- producing or IL-10- treated ILTs. IRF4 knockdown further suppressed survivin expression and the cell growth in these ILTs. These findings indicate that the IL-10-mediated signals promote cell proliferation in HTLV-1-infected cells through the STAT3 and IRF4 pathways. Our results imply that, although HTLV-1 infection alone may not be sufficient for cell proliferation, IL-10 and its signaling pathways within the infected cell itself and/or its surrounding microenvironment may play a critical role in pushing HTLV-1-infected cells towards proliferation at the early stages of HTLV-1 leukemogenesis. This study provides useful information for understanding of disease mechanisms and disease-prophylactic strategies in HTLV-1 infection. It has been a long-unsolved question why HTLV-1 can cause totally different diseases such as ATL and HAM/TSP, manifesting as malignant lymphoproliferation and chronic inflammation, respectively, without disease-specific viral differences. Although the constitutive NF-κB activation in HTLV-1-infected cells has been implicated for HTLV-1 pathogenesis, NF-κB potentially contributes to both leukemogenesis and inflammation. Here, we report that IL-10 and its downstream STAT3 pathway play a critical role in proliferation of HTLV-1-infected cells. Our finding that IL-10 converted the nature of the poorly proliferative HTLV-1-infected cells from HAM/TSP patients into rapidly-growing cells resembling characteristics of ATL cells implies the importance of the host IL-10-dominant microenvironment in building the proliferative machinery in HTLV-1-infected cells. The positive-feedback regulation between IL-10 and STAT3 would likely accelerate this process. These findings emphasize the importance of the STAT3 pathway in addition to the NF-κB pathway in the process leading to leukemogenesis in HTLV-1 infection. This study provides evidence that the host microenvironment is potentially involved in the disease mechanism, partly explaining the reason for the different disease outcomes in HTLV-1 infection.

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Significance: Human T cell leukemia virus type 1 (HTLV-1) proviral load is associated with the risk of developing HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and several small-scale candidate gene approaches have also identified associations of particular HLA alleles with HAM/TSP risk. However, no large-scale genome-wide association (GWA) studies have been performed to date. By a large-scale GWA study and comprehensive genotyping of classical HLA genes, we found that HLA-DRB1 alleles carrying leucine at the antigen presentation groove domain (DRB1-GB-7-Leu) increased the susceptibility to HAM/TSP. Individuals who were homozygous for DRB1-GB-7-Leu had a ninefold increased odds of developing HAM/TSP. This effect of DRB1-GB-7-Leu was independent of proviral load. These findings identify DRB1-GB-7-Leu as a genetic risk marker of HAM/TSP development.

This was a single-centre, retrospective cohort study of patients diagnosed with HAM/TSP based on the WHO criteria.4 Patients who were continuously treated with oral prednisolone (PSL) therapy and had the following data were enrolled: CXCL10 and neopterin concentrations in the CSF measured before and after the initiation of PSL therapy and serial data of the Osame motor disability score (OMDS) (online supplementary figure S1).5