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Assessing the Innate Sensing of HIV-1 Infected CD4+ T Cells by Plasmacytoid Dendritic Cells Using an Ex vivo Co-culture System.
Published on: September 1, 2015
HIV-1-induced migration of monocyte-derived dendritic cells is associated with differential activation of MAPK
Doris Wilflingseder1, Brigitte Müllauer, Herbert Schramek
1Institute of Hygiene and Social Medicine, Innsbruck Medical University, Ludwig Boltzmann Institute for AIDS Research, Innsbruck, Austria.
Insights
Human immunodeficiency virus (HIV) activates dendritic cells (DCs), promoting their migration to lymphoid tissues. This process, mediated by p38 MAPK, facilitates HIV infection of CD4(+) cells.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus (HIV) infects individuals through mucosal surfaces.
- Dendritic cells (DCs) are key immune cells involved in HIV transmission and transport to lymphoid tissues.
- DC activation is a prerequisite for HIV-induced DC migration.
Purpose of the Study:
- To investigate how HIV-1 activates dendritic cells (DCs) and induces their migration.
- To elucidate the signaling pathways involved in HIV-1-mediated DC activation and migration.
- To determine if HIV-1-induced DC migration leads to productive infection of CD4(+) T cells.
Main Methods:
- Treatment of immature (iDCs) and mature (mDCs) with R5- and X4-tropic HIV-1 strains.
- Analysis of DC activation markers (CD83, CD86) and CCR7 expression.
- Assessment of mitogen-activated protein kinase (MAPK) pathways, including p44/p42 ERK1/2 and p38 MAPK.
- Inhibition of p38 MAPK activity using specific inhibitors.
- Chemotaxis assays using chemokines CCL21 and CCL19.
- Co-culture of migrating DCs with peripheral blood lymphocytes (PBLs) to assess infectivity.
Main Results:
- HIV-1 partially up-regulated DC activation markers (CD83, CD86) and CCR7 in two-thirds of donors.
- HIV-1 induced transient p44/p42 ERK1/2 phosphorylation in iDCs and p38 MAPK activation in both iDCs and mDCs.
- p38 MAPK inhibition blocked HIV-1-induced up-regulation of CD83 and CD86.
- HIV-1-induced CCR7 expression facilitated DC migration towards CCL21 and CCL19.
- p38 MAPK inhibition abrogated CCR7-dependent DC migration.
- Migrating DCs successfully infected autologous unstimulated CD4(+) PBLs.
Conclusions:
- HIV-1 manipulates DC signaling pathways, specifically activating p38 MAPK.
- This activation leads to increased CCR7 expression, promoting DC migration along chemokine gradients.
- HIV-1-infected migrating DCs efficiently transmit the virus to nonstimulated CD4(+) T cells, contributing to viral spread.
Abstract:
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.
