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

Florent Percher; Céline Curis; Eléonore Pérès; Maria Artesi; Nicolas Rosewick; Patricia Jeannin; Antoine Gessain; Olivier Gout; Renaud Mahieux; Pierre-Emmanuel Ceccaldi; Anne Van den Broeke; Madeleine Duc Dodon; Philippe V Afonso

doi:10.1038/ncomms15890

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

Nat Commun. 2017 Jun 22:8:15890. doi: 10.1038/ncomms15890.

Authors

Florent Percher^{1

2

3}, Céline Curis^{1

2

3}, Eléonore Pérès⁴, Maria Artesi⁵, Nicolas Rosewick^{5

6}, Patricia Jeannin^{1

2}, Antoine Gessain^{1

2}, Olivier Gout⁷, Renaud Mahieux⁸, Pierre-Emmanuel Ceccaldi^{1

2

3}, Anne Van den Broeke^{5

6}, Madeleine Duc Dodon⁴, Philippe V Afonso^{1

2}

Affiliations

¹ Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris F-75015, France.
² Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris F-75015, France.
³ Université Paris Diderot, Sorbonne Paris Cité, Paris F-75013, France.
⁴ Laboratoire de Biologie et Modélisation de la Cellule, ENS de Lyon, INSERM U1210 CNRS-UCBL UMR 5239, UMS 3444 SFR Biosciences-Lyon, Lyon F-69007, France.
⁵ Unit of Animal Genomics, Groupe Interdisciplinaire Génoprotéomique Appliquée (GIGA), Université de Liège, Liège B-4000, Belgium.
⁶ Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels B-1000, Belgium.
⁷ Service de Neurologie, Fondation Ophtalmologique Adolphe de Rothschild, Paris F-75019, France.
⁸ Equipe Oncogenèse Rétrovirale, ENS de Lyon, and Equipe Labélisée Ligue Nationale Contre le Cancer, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR 5308, Lyon F-69007, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CREB1 protein, human
Cyclic AMP Response Element-Binding Protein
Gene Products, tax
Indoles
Lipoxygenase Inhibitors
NF-kappa B
tax protein, Human T-lymphotrophic virus 1
MK-886
Leukotriene B4
PLA2G4C protein, human
Group IV Phospholipases A2