Integrin and Defensin Modulate the Mechanical Properties of Adenovirus

Abstract

The propensity for capsid disassembly and uncoating of human adenovirus is modulated by interactions with host cell molecules like integrins and alpha defensins. Here, we use atomic force microscopy (AFM) nanoindentation to elucidate, at the single-particle level, the mechanism by which binding of these host molecules affects virus particle elasticity. Our results demonstrate the direct link between integrin or defensin binding and the mechanical properties of the virus. We show that the structure and geometry of adenovirus result in an anisotropic elastic response that relates to icosahedral symmetry. This elastic response changes upon binding host molecules. Whereas integrin binding softens the vertex regions, binding of a human alpha defensin has exactly the opposite effect. Our results reveal that the ability of these host molecules to influence adenovirus disassembly correlates with a direct effect on the elastic strength of the penton region. Host factors that influence adenovirus infectivity thus modulate the elastic properties of the capsid. Our findings reveal a direct link between virus-host interactions and capsid mechanics. Human adenovirus (HAdV) is one of the largest known nonenveloped double-stranded DNA (dsDNA) viruses. The ϳ36-kb viral genome is encapsidated by a pseudo-Tϭ25 icosahedral capsid that is over 90 nm in diameter with a corresponding mass of ϳ150 MDa (1-3). The main capsid proteins form a closed icosahedral shell that is composed of 240 trimeric hexons, 12 pentamers of the penton base, and 12 fiber trimers. In addition, there are four cement capsid proteins (IIIa, VI, VIII, and IX) and five proteins associated with the genomic core of the virion (V, VII, , IVa2, and terminal protein). During the final step of particle maturation, multiple capsid proteins are posttranslationally processed by a viral protease. Approximately one-third of the more than 50 adenovirus types cause acute infections in humans that are generally self-limiting except in immunocompromised patients. Replication-defective adenoviruses are also used in a significant number of gene therapy and vaccine applications (4).Integrin ␣v␤5 is one of several cell surface receptors for adenovirus that mediates internalization of the virus rather than attachment (5-7). Adenovirus binding to integrin ␣v␤5 promotes clustering of the receptors and activates downstream signaling pathways that facilitate virus endocytosis. Integrin binds to exposed RGD motifs on the virus penton base in a maximum stoichiometry of 4:5 (8, 9). This stoichiometric mismatch between integrin ␣v␤5 and the penton base is the result of a steric hindrance. It is also believed that integrin binding causes a conformation change in the penton base. The spiral untwisting of the penton base protein due to integrin binding could relax the interactions of the individual penton base subunits with the neighboring peripentonal hexons as well as cause the release of the fiber protein at the cell surface, thereby facilitating capsid disassembly at a later stage of cell ...

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