The inhibition of chloroquine on pDC activation and its role in the disease progression in the SIV infected Chinese rhesus macaques In this dissertation, two independent parts are included: late SIVmac239 infected Chinese rhesus macaques showed high immune activation; the inhibition of chloroquine on the pDC activation and its role in the disease progression in the SIV infected Chinese rhesus macaques. In the recent several years, it is widely accepted the immune activation contribute a great deal to the severe loss of the CD4+ T cells and the progression to AIDS in the HIV infected individuals. However, the mechanism which leads to this obvious immune activation during HIV infection remains indistinct. Experimental data from many laboratories suggested the activation of the pDCs by the plasma viremia may play a critical role in the immune activation. The HIV can be identified by the Toll like receptor 7 or 9 in the pDCs after its entry into the endosoma through endocytosis. Then the subsequent factors interact with the TLR7/9 and turn on the TLR pathway. At last, the plasmacytoid dendritic cells were activated and large numbers of the type-I interferon are secreted. These high levels of the IFN-I can stimulate the CD4+ T cells, CD8+ T cells, monocytes and other important cell subsets of the immune system which showed an activation phenotype subsequently. The impact of the IFN-I may include the functions, lives and other important properties of the targeted cells. Then, it leads to the rapid progression to AIDS. In addition, there are also many researchers considering the high levels of LPS during HIV infection may be one important cause of the immune activation. As a result, a deep understand of the relationship between immune activation and AIDS may help us to investigate the mechanisms of AIDS and develop effective therapy strategies against it. Our laboratory has established the SIV infected Chinese rhesus macaques as a standard non-human primate AIDS model which can be used to investigate the mechanisms of AIDS. In this study, we have investigated the SIVmac239 infected Chinese rhesus macaques had a higher immune activation phenotype compared with the control animals. The activation of pDC and T cells and also the apoptosis level of T lymphocytes became more severe in the late SIV infected macaques, which suggested the immune activation may lead to the rapid progression to AIDS. We evaluated the immune activation inhibiting function of chloroquine in vitro and in vivo.Chloroquine can block the TLR mediated pDC activation by inhibiting the acidification of the endosome in pDC. Our work clearly showed the chloroquine could effectively inhibit the pDC activation and alpha-IFN production mediated by TLR ligands and the concentrated SIV viral particles. However, there were no evident differences in the T cell activation and the viral load after 30 days chloroquine treatment on the SIVmac239 infected Chinese rhesus macaques. Our work provides valuable data for the research on the mechanism of AIDS and we also tested the validity of chloroquine to be used as an effective drug due to its potential function to inhibit the pDC activation. Our work has a valuable contribution to the further investigation of AIDS mechanisms and its clinical therapy strategies. Keywords: AIDS; HIV-1; SIV; immune activation; pDC; chloroquine; Chinese rhesus macaques
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