Étude du rôle de la protéine Vpr du VIH-1 dans la modulation de la réponse immunitaire
Chronic immune activation and gradual depletion of CD4+ T cells are hallmarks of HIV-1 infection, which are thought to contribute to the progressive deterioration of the host’s immune response that ultimately leads to AIDS. Paradoxically, the majority of CD4+ T cells that are destroyed are uninfected and causes for this bystander effect of infection on CD4+ T cells remains unclear. Some HIV-1 proteins, including the accessory protein Vpr, are suspected to play a role in this process. Vpr, expressed late during HIV-1 infection, is shown to be incorporated within the budding virions as well as secreted as soluble protein in the extracellular medium from the infected cells. The main biological function of Vpr is the induction of a G2/M cell-cycle arrest through the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and activation of the ATR-mediated DNA damage pathway. One study showed that activation of DNA damage pathways leads to the expression of specific ligands for the activating receptor NKG2D expressed on NK cells, thus triggering NK cell cytolytic function. Interestingly, several evidences suggest that HIV-1 upregulates expression of specific NKG2D ligands on infected CD4+ T cells. However, the viral factor involved in this process remains undefined. The aim of this thesis was to evaluate the role of Vpr in modulating NK cell cytolytic function and its potential involvement in CD4+ T cells depletion. Our work demonstrated that the expression of Vpr, alone or in the context of HIV-1 infection, is sufficient to specifically increase expression of the NKG2D ligand, ULBP2, on primary CD4+ T cells. Consequently, these CD4 T cells become more susceptible to autologuous NK cell-mediated lysis. Our studies have shown that this Vpr-mediated ULBP2 upregulation requires the recruitment of the E3 ubiquitin ligase complex DDB1-CUL4AVprBP and the activation of the ATR-mediated DNA damage pathway. More importantly, we provide evidence that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. In that context, we show that delivery of Vpr into uninfected cells via defective viral particles is sufficient to upregulate ULBP2 and increase their susceptibility to autologuous NK cell-mediated killing. In addition, we describe for the first time that soluble Vpr has the ability to induce DNA damages and upregulate ULBP2 upon transducing target cells, including T cells. Overall, our results show that Vpr is a key HIV-1 factor involved in the upregulation of NKG2D ligands induced by HIV-1. This upregulation of UBP2 might contribute to depletion of infected and uninfected CD4 + T cells through activation of NK cell cytolytic functions. A better understanding of the contribution of this new activity of Vpr in HIV-1 pathogenesis has the potential to enable the development of new therapeutic targets or therapeutic strategies against HIV-1.
Virus Vpr ATR ULBP2 NKG2D HIV-1 Accessory proteins NK cells CD4+ T cells depletion