Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

The human immunodeficiency virus type 1 (HIV) establishes a lethal infection by mechanisms that are not clearly understood and viral eradication is not achieved under the current antiretroviral therapies (ART). Potent antiviral responses depend on the ability of antigen presenting cells (APC) to induce antiviral adaptive immunity. Myeloid dendritic cells (DC) are one major type of APC. HIV hijacks the function of DC in adaptive immunity for its own survival advantage. HIV alters the ability to DC to process and present HIV antigens and thus DC fail to induce potent anti-HIV T-cell responses. In addition, DC transmit efficiently virions to CD4+ T-cells and therefore contribute to viral dissemination and persistence. Circulating monocytes are precursors for DC and are used in cell-based immune therapies against cancer and HIV infection. Monocytes are heterogeneous in their stage of differentiation and immunological function. HIV disease progression is associated with the dramatic expansion of a subset of monocytes expressing the molecule CD16 (up to 50% in AIDS patients). Our previous reports demonstrated that CD16+ monocytes, as opposed to CD16- monocytes, are a source of pro-inflammatory molecules and selectively contribute to HIV dissemination in CD4+ T-cells. This project is based on the hypothesis that DC derived from CD16+ monocytes play a deleterious role in HIV pathogenesis, while those derived from CD16- monocytes are able to degrade HIV and prime efficient HIV-specific T-cell responses. Our objective is to identify the molecular basis of these differences by using a systems biology approach. This knowledge will suggest new therapeutic strategies against HIV aimed at interfering with CD16+ monocyte deleterious function. The expected results will recommend the use of CD16- monocytes in DC-based therapies to promote potent anti-HIV immunity, while avoiding viral dissemination.