Mechanism Of Circulating Myeloid Dendritic Cells Depletion In HIV-infected Patients And Fuctional Changes Of Myeloid Dendritic Cells In HIV-infection

HIV/AIDS has become an infectious disease that threatens human health worldwide since its first report in1981. The immune response against HIV infection plays an important role in determining the prognosis of HIV-infected patients. Myeloid dendritic cells (mDC) as an antigen presenting cells, is a bridge connecting the innate and adaptive immunity. Reduced mDC numbers in circulation of HIV-infected patients have been reported by several different groups while its mechanism remain unclear. Meanwhile, the dysfunction of mDC during HIV infection are still not fully understood. Our study is to further clarify the mechanisms of mDC depletion in the circulation of HIV-infected patients and the functional changes of mDC in HIV infection.Part One:We and other researchers previously reported that mDC numbers in the circulation of HIV-infected patients were reduced. However, the mechanisms of mDC depletion remain unclear. We conducted this study to clarify whether apoptosis plays a role in mDC depletion in HIV-infection. PBMC were collected from14HIV-infected patients and10healthy controls. The expression of active caspase8and caspase9in mDC were detected by flow cytometry. The expression of FAS, DR4, DR5, FASL as well as TRAIL were also assessed. We found that the frequencies of mDC in the blood of HIV-infected patients were decreased while the expression of CCR7were up-regulated. The majorities of mDC from HIV-infected patients expressed active caspase8and caspase9. The mDC counts in HIV-infected patients were negatively correlated with the proportion of caspase8+mDC but not the proportion of caspase9+mDC. The proportions of caspase8+and caspase9+mDC were significantly higher than that in healthy controls. B cells and T cells from HIV-infected patients also showed proapoptotic profiles. Percentages of FASL expression mDC were elevated in HIV-infected individuals while the frequencies of mDC that express death receptors were comparable to healthy controls. Caspase8and caspase9expression were up-regulated in mDC isolated from14healthy donors after co-cultured with HIV-1Bal for5days. Our results showed that apoptosis plays an important role in mDC depletion during chronic HIV infection with both extrinsic and intrinsic pathway involved. Apoptosis, especially the activation of extrinsic apoptosis pathway significantly influence the number of mDC in circulation in HIV-infected patients. Meanwhile, migration to lymphoid node is a cause of mDC decreasing in the blood of HIV-infected patients.Part Two:During chronic HIV infection, weak immune responses initialed by mDC would fail to control HIV replication while strong immune responses might result in systemic immune activation. The functional changes of mDC in HIV-infected patients are still controversial. Meanwhile, HIV stimulated pDC could induce Treg generation through IDO pathway which lead to Th17/Treg imbalance. While the expression of IDO in mDC were reported to be higher than pDC in HIV infection, the role of mDC in Th17/Treg balance still need to be established. We conducted this study to clarify the mDC functional changes of mDC as well as its impact in Th17/Treg balance in HIV infection. mDC were isolated from10healthy donors and divided into HIV group and control group. For the HIV group, mDC were stimulated with HIV-Bal while control group were cultured with medium. Mixed lymphocyte reaction were performed using mDC and allogeneic naive T cells. After co-cultured for5days, the proliferation of naive T cells as well as the proportions of Th17and Treg were assessed. We found that naive T cells from HIV group showed higher level of proliferation than that from control group while the proportion of HLA-DR+CD38+CD8T cells were comparable to that from control group. The proportion of Th17and Treg as well as Th17/Treg ratio were comparable between these two groups. Our results suggested that HIV stimulation could enhance the capacity of mDC to stimulate higher level of T cells proliferation. Thus, mDC might play an important role in system immune activation of HIV infection. We failed to found any impact of mDC in Th17/Treg balance. The mechanism of Th17/Treg imbalance in HIV infection need further investigation.