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J. Biol. Chem., Vol. 279, Issue 49, 51305-51314, December 3, 2004

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High Level of Coreceptor-independent HIV Transfer Induced by Contacts between Primary CD4 T Cells^*

Julià Blanco, Researcher of the Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, FIS 98/3047, Berta Bosch, María Teresa Fernández-Figueras¶, Jordi Barretina||, Bonaventura Clotet, and José A. Esté

From the Retrovirology Laboratory, Fundació irsiCaixa and the ^¶Department of Pathology, Hospital Universitari Germans Trias i Pujol, Badalona 08916, Barcelona, Catalonia, Spain

Cell-to-cell virus transmission is one of the most efficient mechanisms of human immunodeficiency virus (HIV) spread, requires CD4 and coreceptor expression in target cells, and may also lead to syncytium formation and cell death. Here, we show that in addition to this classical coreceptor-mediated transmission, the contact between HIV-producing cells and primary CD4 T cells lacking the appropriate coreceptor induced the uptake of HIV particles by target cells in the absence of membrane fusion or productive HIV replication. HIV uptake by CD4 T cells required cellular contacts mediated by the binding of gp120 to CD4 and intact actin cytoskeleton. HIV antigens taken up by CD4 T cells were rapidly endocytosed to trypsin-resistant compartments inducing a partial disappearance of CD4 molecules from the cell surface. Once the cellular contact was stopped, captured HIV were released as infectious particles. Electron microscopy revealed that HIV particles attached to the surface of target cells and accumulated in large (0.5–1.0 µm) intracellular vesicles containing 1–14 virions, without any evidence for massive clathrin-mediated HIV endocytosis. The capture of HIV particles into trypsin-resistant compartments required the availability of the gp120 binding site of CD4 but was independent of the intracytoplasmic tail of CD4. In conclusion, we describe a novel mechanism of HIV transmission, activated by the contact of infected and uninfected primary CD4 T cells, by which HIV could exploit CD4 T cells lacking the appropriate coreceptor as an itinerant virus reservoir.

Received for publication, July 28, 2004 , and in revised form, September 1, 2004.

^* This work was supported in part by Spanish Fondo de Investigaciones Sanitarias (FIS) Project 02/0879, the Red de Investigación del SIDA-RIS network, Ministerio de Educación y Ciencia Project BFI-2003-00405, and European TRIoH Consortium European Union Project LSHG-2003-503480). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Recipient of Fondo de Investigaciones Sanitarias Predoctoral Scholarship 99/9226.

To whom correspondence should be addressed: Laboratori de Retrovirologia, Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n, Badalona 08916, Barcelona, Catalonia, Spain. Tel.: 34-93-465-6374; Fax: 34-93-465-3968; E-mail: jblanco{at}ns.hugtip.scs.es.

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