4 production of over 50 viral proteins, 11 of which are structural virion proteins that produce the characteristic non-enveloped icosahedral protein capsid (Stewart et al. 1993). The capsid consists of three main proteins: hexon, penton base and knobbed fibre proteins (which extend from the penton base). The fibre proteins differ in length depending on the serotype. There are over 100 adenoviral serotypes identified that can infect and replicate in a wide range of organs (Verma and Weitzman 2005). This includes 51 human serotypes (HAd) that are classified into six distinct subgroups (A–F) based on their hemagglutination properties, oncogenic potential, genomic organisation and DNA homology (Arnberg 2009; Sharma et al. 2009). These subgroups exhibit distinct tissue tropism and clinical manifestations (Segerman et al. 2003a; Wadell et al. 1980). The majority of gene transfer studies utilising adenoviral vectors are derived from human Ad serotype 5 (HAd5), although Ad vectors have been generated from other serotypes (including human Ad2, Ad7 and Ad4 as well as non-human viruses). Infection of host cells by wild-type Ads is mediated via cell surface receptors. The efficiency of Ad binding and entry to particular cell types is directly related to the distribution of specific receptors on the cell membrane (Mentel et al. 1997; Russell 2000) and the affinity of the different Ad subgroups to its primary receptor. For the majority of Ad serotypes (HAd2, HAd5, subgroups A, D, E and F but not of subgroup B, as well as serotypes from non-human species), the major cell surface receptor is the Coxsackie adenovirus receptor (CAR; Bergelson et al. 1997; Roelvink et al. 1998). The carboxy-terminal knob domain of the fibre protein (that projects from the adenovirus capsid) binds the CAR with high affinity (Nemerow 2000). Binding between a critical RGD recognition motif in the virus penton base (Stewart et al. 1997) and with the secondary cellular integrin receptors, αvβ3, αvβ5 (Wickham et al. 1993), αvβ1 (Li et al. 2001), α3β1 (Salone et al. 2003) and α5β1 (Davison et al. 2001) has also been shown to occur. Following this binding, viral internalisation proceeds via clathrin-mediated endocy- tosis (Wang et al. 1998). Recent studies are now elucidating additional receptors for various HAd serotypes, especially subgroup B. One main receptor is CD46, a ubiqui- tously expressed type I transmembrane glycoprotein that is a known receptor for a number of other human pathogen (Cattaneo 2004). CD46 has been identified Cell Biol Toxicol (2010) 26:1–20 as a cellular receptor for the majority of subgroup B HAds, including HAd3, HAd7, HAd16, HAd21, HAd50 (subspecies B1), HAd11, HAd14, HAd34 and HAd35 (subspecies B2) (Fleischli et al. 2007; Segerman et al. 2003a, b; Sharma et al. 2009), although CD46 usage by HAd3 and HAd7 remains controversial (Marttila et al. 2005; Tuve et al. 2006). In addition, subgroup D HAds (e.g. HAd37 and HAd49) has also been suggested to use CD46 as an attachment receptor (Lemckert et al. 2006; Wu et al. 2004). Additional cell surface molecules that act directly as attachment or internalisation receptors or indirectly (assisting CAR accessibility to the Ad fibre) have also been identified (Arnberg 2009). These include CD80, CD86, sialic acid, proteoglycans, major histocompatibility complex class I and vascular cell adhesion molecule I. In some cases (e.g. sialic acid), these molecules act as cellular receptors for other viruses, including influenza virus, rotavirus, cornavirus and polyomavirus (Dormitzer et al. 2002; Stehle and Harrison 1997; Weis et al. 1988), whereas the interaction with CD80 and CD86 appears to be specific to certain adenoviral subgroups, e.g. sub- group B. Cells of hematopoietic origin and neoplastic are readily transduced by subgroup B due to high levels of CD80/86 expression (Knaan-Shanzer et al. 2001; Rea et al. 2001; Short et al. 2004). Such research has prompted the proposal of an alternative classification of subgroup B HAds based on their receptor usage (Tuve et al. 2006), and it is hoped that further understanding of subgroup B HAd internal- isation will advance the design of novel Ad vectors for gene delivery. Such understanding also has implications for the usage of research models. For example, the low CD46 expression on rodent cells and low homology between human and rodent CD46 means that rodents do not serve as an ideal model for subgroup B HAds. However, CD46 transgenic mouse models that have CD46 expression profile similar to monkeys and humans have been produced to serve as a suitable preclinical model for CD46-binding Ad vectors (Sakurai et al. 2006; Tatsis et al. 2007). Once inside the cell, the virus-encoded protease assists in the gradual disruption of the virus capsid by proteolysis of viral structural proteins (Greber et al. 1997). This allows the partially disrupted virus to be transported to the nuclear membrane via the partici- pation of dynein and microtubules (Leopold et al. 2000). The viral particle, consisting of viral DNA and