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Journal of Virology, February 2005, p. 2604-2613, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2604-2613.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Early Steps of Clathrin-Mediated Endocytosis Involved in Phagosomal Escape of Fc Receptor-Targeted Adenovirus

Zoologisches Institut,¹ Institut für Molekularbiologie, University of Zürich, Zürich, Switzerland²

Received 21 August 2004/ Accepted 21 September 2004

Adenovirus type 2 (Ad2) and Ad5 enter epithelial cells via the coxsackievirus B Ad receptor (CAR) and _v integrin coreceptors. In the absence of CAR, they can be directed to the Fc receptor 1 of hematopoietic cells by an adaptor comprising the extracellular CAR domain and the Fc portion of a human immunoglobulin G (CARex-Fc). This gives rise to Ad aggregates and single particles which together enhance gene delivery up to 250-fold compared to adaptor-less viruses. A small interfering RNA knockdown of the clathrin heavy chain and quantitative electron microscopy of hematopoietic leukemia cells showed that the majority of Ads were phagocytosed as clusters of 1 to 3 µm in diameter and that about 10% of the particles entered cells by clathrin-mediated endocytosis. The clathrin knockdown did not affect phagocytosis but, surprisingly, inhibited viral escape from phagosomes. Similarly, blocking an early stage of clathrin-coated pit assembly inhibited phagosomal escape and infection but not aggregate uptake, unlike blocking of a late stage of clathrin-coated pit formation. We propose a cooperative interaction of clathrin-mediated endocytosis and phagocytosis triggering phagosomal lysis and infection.

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