HIV Type 1-Infected Dendritic Cells Induce Apoptotic Death in Infected and Uninfected Primary CD4 T Lymphocytes

Abstract

In addition to their essential role in adaptive immunity, dendritic cells (DCs) participate in innate immunity. In the context of measles virus (MV) or cytomegalovirus infections, they develop cytotoxic functions that may contribute in vivo to the elimination of virus-infected cells, but that also kill infected and noninfected T lymphocytes. Because the human immunodeficiency virus (HIV) induces T cell depletion through mechanisms that are still obscure, we investigated its ability to trigger DC cytotoxicity. When incubated with HIV, monocyte-derived DCs induced apoptosis in MDA-231 cells, which are sensitive to MV-induced DC cytotoxicity, and in uninfected as well as HIV-infected H9 CD4⁺ T cell lines. This apoptosis was inhibited by a mixture of FasL, TRAIL, TNF-α, and TWEAK inhibitors. Indeed, HIV infection induced or enhanced sensitivity to TRAIL, TNF-α, and TWEAK in H9 cells. Moreover, dendritic cells incubated with HIV-1 BAL or a wildtype HIV-1 isolate induced apoptosis in autologous primary CD4⁺ T lymphocytes, infected or not with a wild-type HIV-1 isolate. Therefore, induction of DC cytotoxicity by HIV may be relevant to in vivo HIV infection. Induction of cytotoxicity in DCs by HIV might contribute to HIV-associated T cell depletion through induction of apoptosis, especially in the early stages of infection. It may also contribute to elimination of infected cells in vivo, thereby enhancing cross-presentation of HIV by DCs. Therefore this new cytotoxic function of DCs may play an important role in innate and adaptive immunity during HIV infection.