HTLV-I Production Based on Activation of Integrin/Ligand Signaling in HTLV-I-Infected T Cell Lines Derived from HAM/TSP Patients

Abstract

Objective: Activity of integrin/ligand signaling leading to activation of small GTPases might regulate the efficiency of cell-to-cell spread of human T lymphotropic virus type I (HTLV-I) through the virological synapse. We compared both activity of small GTPases and involvement of integrin/ligand signaling in extracellular release of HTLV-I virions between each three HTLV-I-infected T cell lines derived from HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and from other origins as a control. Methods: Activity of small GTPases (Rho, Rac and Cdc42) was analyzed by pull-down assay with suppressive effect of both HTLV-I production and HTLV-I tax mRNA expression by anti-integrin-blocking antibodies. Results: All small GTPases were strongly activated in all cell lines derived from HAM/TSP patients, but not in control cell lines except one cell line. Treatment of all cell lines derived from HAM/TSP patients, but not all control cell lines, with anti-integrin-blocking antibodies significantly suppressed the level of HTLV-I p19 antigen in culture supernatants without downregulation of HTLV-I tax mRNA expression. Conclusion: Significant involvement with integrin/ligand signaling in extracellular release of HTLV-I virions in cell lines derived from HAM/TSP patients suggests that HTLV-I-infected cells in HAM/TSP patients have the potential for the efficient spread of HTLV-I to uninfected cells.

Involvement of C‐X‐C chemokine receptor type 4 signaling in the efficiency of intercellular transmission of human T‐lymphotropic virus type I

“…Previously, we reported that activation of integrin/ligand followed by activation of small GTPases, such as Rac and Cdc42, can contribute to efficient intercellular transmission of HTLV-I. 6 Another small GTPase, Rap1, is a potent stimulator of integrins, such as aLb2 and very late antigen 4, and facilitates inside-out signaling. 8,13 Hence, CXCR4 signaling upstream of Rap1 could also contribute to efficient intercellular transmission of HTLV-I.…”

Intracellular cyclic adenosine monophosphate regulates the efficiency of intercellular transmission of human T‐lymphotropic virus type I

“…However, the increased proliferation of HTLV‐I‐infected cells seems to play a highly important role in this effect, and it can be speculated that efficient intercellular transmission of HTLV‐I is also partially responsible. Indeed, we previously reported that HTLV‐I production by HAM/TSP patient‐derived HTLV‐I‐infected T‐cell lines, in which Rac and Cdc42 are activated, is downregulated by blockade of integrin/ligand interactions, suggesting that the extracellular release of HTLV‐I from these HTLV‐I‐infected T‐cell lines depends on the reorganization status of the cytoskeleton after activation of integrin/ligand signaling. Therefore, HAM/TSP‐derived HTLV‐I‐infected T‐cell lines might have the activity of efficient intercellular transmission of HTLV‐I.…”

“…Interleukin‐2 (IL‐2)‐dependent HTLV‐I‐infected T‐cell line derived from the cerebrospinal fluid of an HAM/TSP patient (HCT‐5) and IL‐2‐independent HTLV‐I‐infected T‐cell line derived from an HTLV‐I carrier (TL‐Su) were used in the present study …”

“…Therefore, it can be speculated that the status of cytoskeletal reorganization determines the intercellular transmission efficiency of HTLV‐I. We previously reported that Rac and Cdc42 are more activated in HTLV‐I‐infected T‐cell lines derived from HAM/TSP patients than in those derived from other origins, suggesting that HTLV‐I‐infected T‐cell lines derived from HAM/TSP patients have the potential of the efficient intercellular transmission of HTLV‐I based on activated status of the cytoskeletal reorganization including actin polymerization.…”

Direct Infection of Primary Salivary Gland Epithelial Cells by Human T Lymphotropic Virus Type I in Patients With Sjögren's Syndrome

“…For the coculture of SGECs with HTLV-I-producing T cells, HCT-5 cells (which are derived from the cerebrospinal fluid cells of patients with HAM [14]), were cultured with SGECs for the designated period of time in defined keratinocyte-SFM culture medium. As a control toward HCT-5, the non-HTLV-I-infected T cell line Jurkat was cultured in RPMI 1640 medium with 10% fetal bovine serum.…”