| HIV infection is characterized by progressive loss of CD4+ T cells and activation of the immune system. This immune activation is mediated by a number of factors, including viral proteins like Tat, as well as cytokines and chemokines. We investigated the role of Tat in activating gene expression as well as the role of a chemokine receptor, CXCR4, which is important for entry of HIV and cellular chemotaxis. We have found that CXCR4-mediated entry can occur efficiently in tissue macrophages, despite the view that macrophages are usually only targeted via CCR5. However, CXCR4-mediated entry into either T-cells or macrophages is inefficient in transgenic rats, compared with CCR5-mediated entry. In humans, pathogenic infection via CXCR4 evolves even in the absence of the accessory Nef protein. A splice variant of the ligand of CXCR4, SDF-1gamma, can inhibit HIV Tat-mediated transcription. In contrast, HIV-1 Tat activates the expression of several genes including CXCR4 and Tsg101 by a transcriptional mechanism, leading to increased chemotaxis to SDF-1 and potential dissemination of infected T cells. Our work describes a complex interplay of HIV proteins, chemokines, and chemokine receptors, in which activation of chemokine-mediated pathways facilitates the pathogenesis of HIV. |
