Actin Reorganization Adenovirus Internalization

Figure 1 Schematic diagram of adenovirus cell entry events. Virus attachment is mediated by fiber protein (black) association with CAR. Subsequent interaction of the penton base (light gray) with av integrins (dark gray) promotes Ad internalization. Integrin-mediated Ad internalization also requires the participation of several signaling molecules (c-Src, pi 30CAS, PI 3K, and Rho GTPAses) that mediate actin polymerization.

molecules including phosphatidylinositol 3-OH kinase [18], a lipid kinase that regulates a number of important host cell functions. These signaling proteins form a complex that promotes the polymerization of cortical actin filaments needed to efficiently internalize virus particles [16, 19]. Similar processes are used for cell invasion by a number of pathogenic bacteria [20, 21]. While the role of actin in virus or bacteria cell entry has not been clearly defined, polymerized actin filaments may serve as a scaffold to prolong the half-life of signaling complexes or they may provide the mechanical force necessary for the formation of endocytic vacuoles [22-24].

An important step of Ad entry postinternalization involves disruption of the early endosome allowing escape of virions into the cytoplasm prior to degradation by lysosomal proteases [25-27]. As is the case for many nonen-veloped viruses, the precise mechanisms involved in Ad-mediated endosome penetration remain poorly defined. The majority of studies indicate that exposure of the virus to mildly acidic conditions (~pH 6.0) are sufficient to initiate the loss of key virus coat proteins as well as activate the viral encoded cysteine protease. However, there is not complete agreement on the requirement for a proton gradient in the early endosome to initiate its disruption [28]. Following endosome disruption, adenovirus particles are rapidly (30-60 min) translocated from the cytoplasm to the nucleus. Transmission electron micrographs obtained by several investigators have shown that viral capsids are docked at the nuclear pore complex [29, 30]. Current information indicates that virus association with microtubules [31] may play a key role in nuclear transport. Biochemical analyses have indicated that the majority of the viral capsid remains in the cytoplasm during transport of the viral genome into the nucleus [32]. This latter process appears to require the major host cell factors involved in nuclear import, the heat-shock p70 protein (Hsp70) and perhaps other cellular factors [33]. Viral gene expression and/or viral replication takes place once nuclear transport has occurred and ultimately results in the generation of transgene products in the case of viral vectors or in progeny virions in the case of wild-type particles. As is the case with many human pathogens, important questions remain to be answered regarding the precise mechanisms involved in each step of adenovirus cell entry.

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