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.
Highlights
The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts
It was previously reported that, on ionomycin stimulation, PBMCs isolated from HTLV-1-infected individuals secrete significantly more leukotriene B4 (LTB4) than PBMCs from uninfected healthy donors (HDs)[20]
Considering the proportion of CD4 T cells among PBMCs for the different donors, we estimated that 20–30% of the LTB4 spontaneously released by PBMCs is produced by CD4 T cells in HTLV-1 asymptomatic carriers (HACs); in HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), secretion by CD4 T cells accounts for 80% of the LTB4 released by PBMCs
Summary
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. We demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4). 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. Previous studies have demonstrated that HTLV-1-infected cells have an increased migratory capacity, which may facilitate the encounter with potential target cells[16,17,18]. We postulate that target cells are recruited to the vicinity of HTLV-1-infected cells through the effect of chemoattractants released by the latter[19]
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