NK-DC cross talk contributes to HIV replication through HMGB1. The mechanisms involved in NK-DC interaction during viral infections are poorly understood. It was recently reported in murine CMV (MCMV) infection that MCMVinfected DCs were capable of activating syngeneic NK cells in vitro and also capable of enhancing NK-dependent clearance in vivo, 85 demonstrating the crucial role of NK-DC cross talk in controlling viral replication. In HIV infection, NK-DC interaction was found defective in viremic HIV-1-infected patients, characterized by abnormalities in the process of reciprocal NK-DC activation and maturation. 86 Recently, we investigated the impact of HIV-1 on NKdependent maturation and function of iDCs in an ex-vivo model of cross talk between purified primary NK cells and monocytes-derived iDCs. We discovered that maturation of HIV-1-infected DCs required aNK to occur and this process involved HMGB1. Blocking HMGB1 with specific antibodies or glycyrrhizin, a specific inhibitor of HMGB1, impaired maturation of infected DCs. However, the cross talk between HIV-1-infected DCs and aNK cells was functionally defective, as demonstrated by the strong impairment of DCs to induce Th1 polarization of naïve CD4 T cells. This was associated with the defective production of IL-12 and IL-18 by infected DCs, known to trigger the adaptive response. 21 Moreover, the interaction between aNK and HIV-1-infected DCs resulted in a dramatic increase in viral replication and proviral DNA expression in DCs. This process was mainly triggered by HMGB1, released both by NK cells and DCs, and blocking HMGB1 strongly inhibited HIV replication in both isolated infected DCs and DCs cocultured with aNK cells 21 (Figure 4) . Thus, these findings provide evidence for the crucial role of NK-DC cross talk in promoting viral dissemination, and challenge the question of the in vivo involvement of HMGB1 in the triggering of HIV-1 replication and replenishment of viral reservoirs in AIDS. NK-DC cross talk and HMGB-dependent HIV persistence in DCs. The NK cell-mediated editing process of DCs, which is required to keep in check the quality of DCs prone to mature and further present the antigen to T cells, is compromised during HIV infection. Indeed, NK cells from viremic patients show a decreased ability to kill immature DCs. 87 The defect is associated with an increase in the proportion of CD56 À NK cells with impaired NKp30 function. 86 In addition, increased production of IL-10 during HIV-1 infection can protect immature DCs from NK cellmediated lysis, resulting in accumulation of partially mature, poorly immunogenic DCs in the lymph nodes of infected individuals. 88 In an ex-vivo model of NK-DC cross talk, we showed that HIV-1-infected DCs become resistant to NK cellmediated lysis due to an upregulation in DCs of two apoptosis inhibitors, cellular FLICE-inhibitory protein (cFLIP) and cellular inhibitor of apoptosis protein 2 (c-IAP2). 22 The expression of these inhibitors was upregulated by HMGB1, released by aNK cells at NK-DC synapse, and they protected HIV-1-infected DCs from TRAIL-dependent apoptosis. 22 Blocking HMGB1 with specific antibodies restored the susceptibility of infected DCs to NK killing, and similar effect was observed knocking down c-FLIP or c-IAP2 by siRNA 22 (Figure 5 ). Overall, these findings suggest that impaired NK-DC cross talk during HIV-1 infection is a consequence of bidirectional alteration of both DC and NK cell functions, and they reveal the pivotal role of HMGB1 in HIV-1 persistence in DCs.