HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

Abstract

The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied in vitro, those facilitating the encounter between infected and target cells remain unknown. In this study, we demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4). LTB4 secretion is dependent on Tax-induced transactivation of the pla2g4c gene, which encodes the cytosolic phospholipase A2 gamma. Inhibition of LTB4 secretion or LTB4 receptor knockdown on target cells reduces T-cell recruitment, cellular contact formation and virus propagation in vitro. Finally, blocking the synthesis of LTB4 in a humanized mouse model of HTLV-1 infection significantly reduces proviral load. This results from a decrease in the number of infected clones while their expansion is not impaired. This study shows the critical role of LTB4 secretion in HTLV-1 transmission both in vitro and in vivo.

PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice

“…Several human viruses and among them lymphotropic viruses have been extensively used in these models [ 22 , 23 , 30 ]. Thus, hu-mice have been used to approach the pathogenic activity of HTLV-1 Tax in a more biological model than cultured cells [ 25 – 27 , 31 ]. Here we have investigated the role played by the Tax PBM in the lymphoproliferation triggered by HTLV-1 infection of hu-mice.…”

Monitoring molecular response in adult T-cell leukemia by high-throughput sequencing analysis of HTLV-1 clonality

“… 9 , 10 , 11 In this study, we explored the benefit of an optimized high-throughput sequencing (HTS) clonality method as a quantitative molecular approach to monitor the malignant clone identified at diagnosis and better evaluate therapeutic response. 10 , 12 The method enables the genome-wide mapping of HTLV-1 integration sites and the simultaneous quantification of the abundance of the corresponding clones. It includes several critical modifications that overcome the limitations of previously reported protocols, 13 , 14 increasing sensitivity, facilitating multiplexing, and significantly reducing both the cost and hands-on time ( Supplementary Methods ).…”

The Role of Chemokines in the Pathogenesis of HTLV-1

“…Therefore, the consistent CCR4 expression on ATL cells and HTLV-1 transformed T cells may be attributable to the perception that HTLV-1 preferentially infects CCR4 + T cells through the recruitment of CCR4 + T cells via CCL22 and/or due to some growth advantages of HTLV-1-infected CCR4 + T cells in vivo as well as in vitro (Yoshie et al, 2002). However, Sugata et al (2016) showed that HBZ upregulates CCR4 expression in ATL and HTLV-1 infected cells and thus, migration and proliferation of those cells are increased, thus CCR4 may not be initially expressed on the infected cells (Percher et al, 2017). CD4 + FOXP3 + cells are observed at a high frequency in ATL patients (Toulza et al, 2009).…”