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Is Required for Efficient HIV-1 Entry and Infection of T Cells1
* Servicio de Inmunología, Hospital Universitario de La Princesa, Madrid,
Departamento de Medicina Física y Farmacología. Facultad de Medicina, Universidad de La Laguna, Tenerife, and
Servicio de Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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
. Overexpression of wild-type PI4P5-K I 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 overexpressing the kinase-dead mutant D227A (D/A)-PI4P5-K I. 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. These data indicate that PI4P5-K I-mediated PIP2 production is crucial for HIV-1 entry and the early steps of infection in permissive lymphocytes.
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1 This work was supported by Grants BFU2005-08435/BMC, FIPSE 36289/02 and 36658/07 (Fundación para la Investigación y Prevención del SIDA en España), "Ayuda a la Investigación Básica 2002" (Fundación Juan March), and "Fundación Lilly" (to F.S.-M.). A.V.-F. was supported by Grants FIPSE 24508/05, Fundación Mutua Madrileña, Spain, FIS-PI050995 from the "Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo," Spain, and IDT-TF-06/066 and IDT-TF-06/063 from the "Consejería de Industria, Comercio y Nuevas Tecnologías del Gobierno Autónomo de Canarias," Spain, and "Fondo Social Europeo (RYC2002-3018)."
2 Address correspondence and reprint requests to Francisco Sánchez-Madrid and Agustín Valenzuela-Fernández, Servicio de Inmunología, Hospital Universitario de La Princesa, Madrid, Spain. E-mail addresses: fsanchez.hlpr{at}salud.madrid.org and avalenzu{at}ull.es
3 Abbreviations used in this paper: PIP2, phosphatidylinositol 4,5-biphosphate; PI4P5-K type I, phosphatidylinositol 4-phosphate 5-kinase type I; PHD, pleckstrin homology domain; Env, envelope; wt, wild type; HA, hemagglutinin; MOI, multiplicity of infection; siRNA, short interference RNA.
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