PI4P5-kinase Ialpha 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 (PIP(2)) 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 PIP(2) production in permissive lymphocytes through the activation of phosphatidylinositol-4-phosphate 5-kinase (PI4P5-K) Ialpha. Overexpression of wild-type PI4P5-K Ialpha increased HIV-1 Env-mediated PIP(2) production and enhanced viral replication in primary lymphocytes and CEM T cells, whereas PIP(2) production and HIV-1 infection were both severely reduced in cells overexpressing the kinase-dead mutant D227A (D/A)-PI4P5-K Ialpha. 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 Ialpha. These data indicate that PI4P5-K Ialpha-mediated PIP(2) production is crucial for HIV-1 entry and the early steps of infection in permissive lymphocytes.
Barrero-Villar
Marta
M
Servicio de Inmunología, Hospital Universitario de La Princesa, Madrid, Spain.
Barroso-González
Jonathan
J
Cabrero
J R
JR
Gordón-Alonso
Mónica
M
Alvarez-Losada
Susana
S
Muñoz-Fernández
M A
MA
Sánchez-Madrid
Francisco
F
Valenzuela-Fernández
Agustín
A
D015153:Blotting, Western; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018613:Microscopy, Confocal; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis* / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*
D015699:HIV Envelope Protein gp120; D019269:Phosphatidylinositol 4,5-Diphosphate; C514793:gp120 protein, Human immunodeficiency virus 1; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase