221 HIV Persistence in Dendritic Cells - Contribution of NK Cells and Pivotal Role of HMGB1
Journal of Acquired Immune Deficiency Syndromes(2011)
Abstract
Persistent viruses are able to subvert host antiviral immunity, thereby facilitating viral dissemination. In particular, HIV-1 has evolved ways to exploit dendritic cells (DCs) by blocking the “editing process” that physiologically allows NK cells to keep in check the quality of DCs through their elimination when they are altered. In the context of viral infections, NK-mediated killing of infected DCs is an essential step for early control of viral replication and avoidance of dissemination. In this study, we addressed the question of the impact of HIV-1 infection on DCs' susceptibility to NK killing. We report that uninfected iDCs are susceptible to NK-mediated killing, which involves the TRAIL/DR4 pathway. In contrast, HIV-1-infected DCs become resistant to NK-mediated killing. This is due to the dramatic upregulation of two anti-apoptotic molecules, c-FLIP and c-IAP2, in infected DCs, inducing their resistance to NK (TRAIL)-mediated apoptosis. Interestingly, the alarmin HMGB1, expressed at the synapse between NK cells and DCs, was found to play a pivotal role in this process, and inhibition of its activity by glycyrrhizin or specific antibodies restored NK-dependent killing of infected DCs through the inhibition of c-FLIP and c-IAP2 upregulation. Moreover, the crosstalk between NK cells and infected DCs resulted in a dramatic increase in viral replication in DCs, that was associated with a strong impairment of their ability to induce Th1 polarization. Overall, these observations provide new insights into how HIV hijacks DCs to promote viral persistence and dissemination, and uses NK-DC interaction to promote the survival of infected DCs, thus establishing long-term reservoirs. In addition, they challenge the question of the in vivo involvement of HMGB1 in the triggering of viral replication, the in vivo expression of HMGB1 being correlated with viral load and disease progression.
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Key words
hiv persistence,nk cells,dendritic cells
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