Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells

Abstract

Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1␤ (IL-1␤), IL-1␣, tumor necrosis factor alpha (TNF-␣), TNF-␤, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax 221 ) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of a slow progressive neurological disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (42). Although most HTLV-1-infected individuals remain asymptomatic carriers, an estimated 5 to 10% of HTLV-1-infected individuals develop HAM/TSP. HTLV-2 was originally isolated from a patient with an atypical hairy cell leukemia and shares ca. 70% sequence homology with HTLV-1. To date, HTLV-2 infection has been rarely and controversially linked to the development of neurodegenerative diseases (2, 30).Cytokines play a critical role in physiological processes in the central nervous system (CNS), including establishing and maintaining normal homeostasis, as well as mediating inflammatory and immune responses. Cytokines have also been implicated as being the major mediators of demyelination in the CNS, resulting in a variety of inflammatory and neoplastic diseases (1). Elevated levels of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), IL-1␣, and IL-6 have previously been detected in the cerebrospinal fluid of HAM/TSP patients (28,40,57), suggesting that increased expression of these proi...

Adult T-cell leukemia/lymphoma development in HTLV-1–infected humanized SCID mice

“…[22][23][24] CD34 ϩ HPCs (5 ϫ 10 6 ) were injected into sublethally irradiated (350 rads) 4-to 6-weekold NOD/SCID pkrdc mice (The Jackson Laboratory) intravenously through the tail vein, as previously described [25][26][27] to generate HTLV-1-HU-NOD/ SCID or Tax1-HU-NOD/SCID mice. HTLV-1-infected or mock CD34 ϩ HPCs (2 ϫ 10 5 ) were injected into sublethally irradiated (25 rads) 1-to 2-day-old NSG mice (The Jackson Laboratory) intrahepatically to generate HTLV-1-HU-NSG and mock HU-NSG mice as described previously.…”

“…LVs, which coexpress HTLV-1 tax and green fluorescent protein (GFP; pHR'CMV-Tax1/GFP), have previously been described [22][23][24] and were used to transduce CD34 ϩ HP/HSCs ex vivo before inoculation into NOD/SCID mice. Tax1-HU-NOD/SCID mice developed CD4 ϩ malignancies with a slightly accelerated kinetics in comparison with HTLV-1-HU-NOD/SCID mice (Table 1; Figure 2).…”

Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

“…Retrovirus-mediated Tax expression in Jurkat T cells was reported to induce apoptosis, which is mediated by NF-B-activated expression of TRAIL (71). We examined the TRAIL mRNA expression in LV-Tax-infected U251 cells compared with LV-EGFP-infected ones, while IL-6 mRNA expression, which is reported to be increased in Tax-expressing U251 cells (9), was detected to confirm the function of Tax. Results showed that IL-6 mRNA was upregulated in Tax-expressing U251 cells, but the expression of TRAIL mRNA remains unchanged (data not shown).…”

“…Astrocytes are the most abundant cells in the CNS and perform many functions, including maintaining the physical integrity of the blood-brain barrier (BBB), providing nutrients to neuronal cells, and mediating the extracellular ion balance in the CNS (8). A previous study has shown that the in vitro infection of human astrocytes with HTLV-1 results in the release of proinflammatory cytokines (9). Furthermore, it has been found that neuropilin-1 and glucose transporter protein 1 are involved in HTLV-1 infection of U87 astroglioma cells and human primary astrocytes (10).…”

Tax 1-Independent Induction of Vascular Endothelial Growth Factor in Adult T-Cell Leukemia Caused by Human T-Cell Leukemia Virus Type 1

“…Activation of prosurvival signals such as the NF-B and Akt pathways by Tax 1 plays a critical role in events leading to ATL development and leads to the abnormal expression of several cellular proteins normally involved in apoptosis, cell cycle control, and DNA damage repair (23,34). The upregulation of genes encoding cytokines (1,4,12,33) and growth factors (14,15,27) by Tax 1 is speculated to play a pivotal role in T-cell activation and proliferation and likely contributes to the pathogenesis of both ATL and TSP/HAM.…”