l-663536 and HTLV-I-Infections

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.

Topics: Animals; CD4-Positive T-Lymphocytes; Cyclic AMP Response Element-Binding Protein; Female; Gene Products, tax; Group IV Phospholipases A2; Host-Pathogen Interactions; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Indoles; Infant, Newborn; Jurkat Cells; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice, Mutant Strains; NF-kappa B