HIV-1-induced migration of monocyte-derived dendritic cells is associated with differential activation of MAPK pathways.
From the site of transmission at mucosal surfaces, HIV is thought to be transported by DCs to lymphoid tissues. To initiate migration, HIV needs to activate DCs. This activation, reflected by intra- and extracellular changes in cell phenotype, is investigated in the present study. In two-thirds of the donors, R5- and X4-tropic HIV-1 strains induced partial up-regulation of DC activation markers such as CD83 and CD86. In addition, CCR7 expression was increased. HIV-1 initiated a transient phosphorylation of p44/p42 ERK1/2 in iDCs, whereas p38 MAPK was activated in both iDCs and mDCs. Up-regulation of CD83 and CD86 on DCs was blocked when cells were incubated with specific p38 MAPK inhibitors before HIV-1-addition. CCR7 expression induced by HIV-1 was sufficient to initiate migration of DCs in the presence of secondary lymphoid tissue chemokine (CCL21) and MIP-3beta (CCL19). Preincubation of DCs with a p38 MAPK inhibitor blocked CCR7-dependent DC migration. Migrating DCs were able to induce infection of autologous unstimulated PBLs in the Transwell system. These data indicate that HIV-1 triggers a cell-specific signaling machinery, thereby manipulating DCs to migrate along a chemokine gradient, which results in productive infection of nonstimulated CD4(+) cells.
Wilflingseder
Doris
D
Institute of Hygiene and Social Medicine, Innsbruck Medical University, Ludwig Boltzmann Institute for AIDS Research, Innsbruck, Austria.
Müllauer
Brigitte
B
Schramek
Herbert
H
Banki
Zoltan
Z
Pruenster
Monika
M
Dierich
Manfred P
MP
Stoiber
Heribert
H
D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000821:virology*; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D009000:Monocytes / Q000166:cytology*; D010766:Phosphorylation; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
D015214:Antigens, Differentiation, Myelomonocytic; C515370:CCR7 protein, human; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases