Pathway of Adenovirus Cell Entry

Adenoviruses cause a significant number of acute respiratory, gastrointestinal, and ocular infections in man. While these infections are usually self-limiting they can result in significant morbidity and in immunocompromised individuals are capable of causing fatal disseminated infections [1]. Among the ~50 different adenovirus (Ad) serotypes, representing six different subgroups (A-F) [2, 3], the majority of information on the molecular basis of host cell interactions is derived from studies on the closely related types 2 and 5 (subgroup C) [4]. It is, therefore, not surprising that replication-defective forms of Ad5 are currently being used for most in vitro and in vivo gene delivery applications [5, 6]. Despite some reported successes, adenovirus-mediated gene delivery remains hampered due in large part to the host immune response to viral proteins [7, 8]. Increased knowledge of Ad structure [9, 10] and host cell interactions [11] may allow redesigning of viral vectors in order to avoid some of the major problems in this area.

Ad types 2/5 bind to cells via their fiber protein [12], which recognizes a 46-kDa cell receptor known as CAR (Coxsackie and adenovirus receptor) [13, 14]. However, this high-affinity receptor interaction is unable to promote efficient virus uptake into the host cell. Instead, secondary interactions of the virus penton base protein with av|33 or av|35 integrins facilitates virus internalization [15] (Fig. 1). Adenovirus particles enter cells via ~120 nM clathrin-coated pits and vesicles [16]. Hela cells expressing a mutant form of dynamin; a large GTPase associated with endosome formation, fail to support efficient virus uptake or infection, indicating that clathrin/receptor-mediated endocytosis is the primary pathway of Ad2/5 infection of host cells [17]. Adenovirus internalization also requires the participation of cell signaling

ADENOVIRAL VECTORS FOR GENE THERAPY Copyright 2002, Elsevier Science (USA). All rights reserved.

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