Increased Activity of Extrinsic and Intrinsic Apoptosis Pathways in Different Mononuclear Cell Types in HIV Type 1-Infected Patients Regardless of Whether They Are Depleted in Disease

Abstract

Myeloid dendritic cells (mDCs) are essential for initiation of adaptive immune responses but are depleted in HIV infection. Evidence suggests that apoptosis mediates loss, and to further understand the pathways involved, expression of caspases mediating apoptosis via the extrinsic and intrinsic pathways was analyzed. Blood samples were obtained from 14 HIV-infected patients (nine HAART and five antiretroviral naive) and 10 healthy controls. The expression of intracellular active caspases 8 and 9, associated with extrinsic and intrinsic pathways of apoptosis, and the expression of cell membrane death receptors and their ligands were assessed by flow cytometry in mDC. Additionally, expression of active caspases 8 and 9 in purified mDCs cultured for 5 days with HIV-Bal was analyzed. Frequencies of mDCs in the blood of HIV-infected patients were decreased while expression of CCR7 was up-regulated. Up to 94.4% and 91.8% of mDCs from HIV-infected patients expressed active caspases 8 and 9, respectively, compared to 24.5% and 19.9% from healthy controls (both p<0.0001). However, monocytes and B and T cells from HIV-infected patients also showed increased levels of these caspases. Percentages of FASL expression in mDCs were also elevated in HIV-infected individuals while mDCs expressing cell membrane death receptors remained unchanged. No differences between HAART and naive patients were observed for any of the molecules measured. Caspases 8 and 9 were up-regulated in mDCs cocultured with HIV despite lack of productive infection in vitro. Extrinsic and intrinsic pathways of apoptosis are up-regulated in HIV infection but do not correlate with cell depletion.