P15. Dendritic cell rewiring by HIV.

Aikaterini Nasi1, Sylvie Amu1, Noemi Nagy1, Marianne Jansson2, Francesca Chiodi1 and Bence Réthi1

Affiliates: 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden 2Department of Laboratory Medicine Lund, Lund University, Lund, Sweden

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Background
Dendritic cells (DCs) are potent antigen presenting cells that display altered functions and roles during the course of HIV infection. We have previously established the experimental bases for the generation of functionally different DC types in cell culture. Lactic acid, a side product of glycolytic metabolism, accumulated in dense cultures and induced a robust anti-inflammatory program in the developing cells, leading to suppressed DCs that were unable to migrate towards lymph node chemokines or induce T cell activation and TH1 polarization. On the other hand, DCs developing at low lactic acid levels showed a superior ability to produce inflammatory cytokines, to induce TH1 polarization and to migrate towards lymphoid tissue chemokines. Here we investigate how differentially programmed DCs respond to HIV in order to understand the potential effects of viral DC modulation in shaping immune responses during HIV-1 infection.

Methods
Immunostimulatory or suppressed DCs were generated from human monocytes by exposing the cells to different levels of endogenous lactic acid levels in sparse or dense cultures, respectively. The different DC types were incubated with the HIV-1 isolates IIIB and SF162 and DC functions were analyzed.

Results
Pre-incubation with HIV-1 led to a significantly increased capacity of IL-12 production in the suppressed DC type whereas the same treatment induced a rapid functional exhaustion of inflammatory DCs, indicating profound effects of HIV-1 on the ability of DCs to trigger TH1 responses. The observed rewiring of DC functions occurred independently of DC infection or the HIV-1 binding lectin molecule, DC-SIGN or the rewiring of the IRAK signaling compounds that is often associated with DC exhaustion. In the presence of HIV-1, suppressed DCs were characterized by a persistently increased expression of several cytokine and chemokine genes suggesting a virus-induced activation program that predispose DCs to inflammatory responses. In addition, HIV-1 binding modulated the expression of pyruvate dehydrogenase kinase (PDK)-4, suggesting a virus-induced alteration in DC metabolism.

Conclusions
The effects of HIV-1 on DC activities are strongly influenced by the functional programming of the DCs. The virus-mediated activation of the suppressed DCs suggested progressively increased inflammatory activities and T cell stimulation by resting DC types, which are immunologically inactive under normal circumstances.