Journal
JOURNAL OF VIROLOGY
Volume 80, Issue 18, Pages 8961-8969Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00843-06
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Funding
- NHLBI NIH HHS [P01 HL051818, P01 HL 51818, P01 HL066973, P01 HL 59412, P01 HL 66973, P01 HL059412] Funding Source: Medline
- NIGMS NIH HHS [U24 GM116792] Funding Source: Medline
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Integrins have been implicated as coreceptors in the infectious pathways of several nonenveloped viruses. For example, adenoviruses are known to interact with alpha V integrins by virtue of a high-affinity arginine-glycine-aspartate (RGD) domain present in the penton bases of the capsids. In the case of adeno-associated virus type 2 (AAV2), which lacks this RGD motif, integrin alpha V beta 5 has been identified as a coreceptor for cellular entry. However, the molecular determinants of AAV2 capsid-integrin interactions and the potential exploitation of alternative integrins as coreceptors by AAV2 have not been established thus far. In this report, we demonstrate that integrin alpha 5 beta 1 serves as an alternative coreceptor for AAV2 infection in human embryonic kidney 293 cells. Such interactions appear to be mediated by a highly conserved domain that contains an asparagine-glycine-arginine (NGR) motif known to bind alpha 5 beta 1 integrin with moderate affinity. The mutation of this domain reduces transduction efficiency by an order of magnitude relative to that of wild-type AAV2 vectors in vitro and in vivo. Further characterization of mutant and wild-type AAV2 capsids through transduction assays in cell lines lacking specific integrins, cell adhesion studies, and cell surface/solid-phase binding assays confirmed the role of the NGR domain in promoting AAV2-integrin interactions. Molecular modeling studies suggest that NGR residues form a surface loop close to the threefold axis of symmetry adjacent to residues previously implicated in binding heparan sulfate, the primary receptor for AAV2. The aforementioned results suggest that the internalization of AAV2 in 293 cells might follow a click-to-fit mechanism that involves the cooperative binding of heparan sulfate and alpha 5 beta 1 integrin by the AAV2 capsids.
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