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HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy.

ABSTRACT: Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.

SUBMITTER: Maher AK

PROVIDER: S-EPMC10906466 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy.

Maher Allison K AK Aristodemou Aris A Giang Nicolas N Tanaka Yuetsu Y Bangham Charles Rm CR Taylor Graham P GP Dominguez-Villar Margarita M

JCI insight 20240109 1

Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher f ...[more]

PMID: 38193535

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Project description:BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown.MethodsIn this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4+ and CD4+CCR4+ cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM.ResultsWe found elevated expression of EZH2 in CD4+ and CD4+CCR4+ cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67+ CD4+ T cells and Ki67+ CD8+ T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(-) early apoptotic cells.ConclusionThis study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.

Project description:Around ten million people are infected with HTLV-1 worldwide, and 1-4% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by an important degeneration of the spinal cord, which can lead to death. Distinct HLA alleles have been associated with either HAM/TSP susceptibility or protection. However, these HLA alleles set may change according to the population studied. Brazil is the second country in the number of HTLV-1-infected people and there are few reports addressing the HLA influence on HTLV-1 infection as well as on disease outcome. The objective of this study was to evaluate the influence of HLA alleles as a risk factor for HAM/TSP and the proviral load (PVL) levels, clinical progression, and death outcomes in an admixed Brazilian population. The HLA-A, -B, -C, and -DRB1 were genotyped in 375 unrelated HTLV-1-infected individuals divided into asymptomatic carriers (AC) (n = 165) and HAM/TSP (n = 210) in a longitudinal cohort from 8 to 22 years of follow-up. Because locus B deviated from Hardy-Weinberg Equilibrium for the study groups, the results represented for HLA-B alleles were inconclusive. The alleles HLA-A*68 and -C*07 were related to HAM/TSP risk in multivariate analysis. The alleles HLA-A*33, and -A*36 were associated with protection against disease progression in HAM/TSP patients, while -C*12, -C*14, and -DRB1*08 were associated with increased risk of death. In the AC group, the presence of, -C*06 and -DRB1*15 alleles influenced an increased PVL, in an adjusted linear regression model, while -A*30, -A*34, -C*06, -C*17 and -DRB1*09 alleles were associated with increased PVL in HAM/TSP group compared to HAM/TSP individuals not carrying these alleles. All these alleles were also related to increased PVL associated with clinical progression outcome. Increased PVL associated with the death outcome was linked to the presence of HLA-A*30. PVL has been associated with HLA, and several alleles were related in AC and HAM/TSP patients with or without interacting with clinical progression outcomes. Understanding the prognostic value of HLA in HAM/TSP pathogenesis can provide important biomarkers tools to improve clinical management and contribute to the discovery of new therapeutic interventions.

Project description:IntroductionGalvanic vestibular stimulation (GVS) is a simple, safe, and noninvasive method of neurostimulation that can be used to improve body balance. Several central nervous system diseases cause alterations in body balance, including HTLV-1-associated myelopathy (HAM).ObjectiveTo test GVS as a balance rehabilitation strategy for HAM.MethodsThis study is a quasi-experimental clinical trial in which postural balance was compared before and after a GVS rehabilitation protocol applied to 20 patients with HAM, 12 women and 8 men, average age of 78 and 79 years, respectively. They were followed for nine months after the end of the GVS protocol, which consisted of one GVS session per week for 12 consecutive weeks. The GVS current intensity was progressively increased from 1.0 milliamperes (mA) to 3.5 mA until the third session and maintained at 3.5 mA until the 12th session. The electrical stimulation time progressively increased from 9 min in the first session to 18 min in the second session and maintained at 30 min from the third session onwards. Postural balance was assessed by Time up and go test (TUG), Berg balance scale (BBS) and posturography that were performed before the beginning of the intervention, during the intervention (6th week), at the end of the intervention (12th week) and after 9 months of follow-up without electrical stimulation.ResultsIn a blind comparison, in the 12th week of stimulation, improvement was observed in all the tests. In TUG, time in seconds changed from 28 before to 18 after GVS (p < 0,001). In BBS, the score changed from 29.00 before to 41.00 points after GVS. In posturography, the stability limit improved after the intervention (p < 0.05). However, after nine months without stimulation, the gain was lost for TUG, for BBS and for stability limit.ConclusionGVS was an effective method to improve postural instability of patients with HAM in the short term, but the gain in postural stability was not maintained in the long term. A device for home use may be an option for long-term use.

Dataset Information

HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy.

Publications

HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy.

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