PI4P5-Kinase Iα Is Required for Efficient HIV-1 Entry and Infection of T Cells

HIV-1 envelope (Env) triggers membrane fusion between the virus and the target cell. The cellular mechanism underlying this process is not well known. Phosphatidylinositol 4,5-bisphosphate (PIP2) is known to be important for the late steps of the HIV-1 infection cycle by promoting Gag localization to the plasma membrane during viral assembly, but it has not been implicated in early stages of HIV-1 membrane-related events. In this study, we show that binding of the initial HIV-1 Env-gp120 protein induces PIP2 production in permissive lymphocytes through the activation of phosphatidylinositol-4-phosphate 5-kinase (PI4P5-K) I alpha. Overexpression of wild-type PI4P5-K I alpha increased HIV-1 Env-mediated PIP2 production and enhanced viral replication in primary lymphocytes and CEM T cells, whereas PIP2 production and HIV-1 infection were both severely reduced in cells over-expressing the kinase-dead mutant D227A (D/A)-PI4P5-K I alpha. Similar results were obtained with replicative and single-cycle HIV-1 particles. HIV-1 infection was also inhibited by knockdown of endogenous expression of PI4P5-K I alpha. These data indicate that PI4P5-K I alpha-mediated PIP2 production is crucial for HIV-1 entry and the early steps of infection in permissive lymphocytes. The Journal of Immunology, 2008, 181: 6882-6888.