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Integrins are a family of ubiquitous α/β heterodimeric glycoproteins that mediate cell migration and adhesion. The major ligands for integrins are coagulation and fibrinolytic factors, complement proteins and cellular counter-receptors, epithelial and vascular matrix components in addition to viral proteins. Integrins and their ligands are currently an intensely investigated topic in fields as hematology, neurobiology, thrombosis, cancer biology, developmental biology, inflammation, gene therapy and viral We have splited the long sentence to short sentences. (2, 4, 18, 19, 20, 22, 30). Increasing evidences have demonstrated that many viruses such as human coxsackievirus A9, human papillomavirus, adenoassociated virus 2 (AAV2), hantaan virus (HT-NV), foot-and-mouth disease virus (FMDV), human parechovirus 1 and human echovirus (1, 8, 9, 22) can initiate infection by attaching to activated integrins. This review focuses on recent advances relating to factors contributing to intergrin activation and the roles of integrins in viral infection.
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Many viruses exploit the endocytic machinery of the host for invasion in which viruses must attach to the specific receptor(s) on the cell surface. These receptors usually play important roles in cell adhesion, cell-cell interactions, signalling and defence mechanisms. The binding of a virus to a receptor can elicit changes in receptor conformation. These alterations may bring about signalling events which regulate both the viral entry and the cellular response to the infection (13, 21). In addition, conformational changes in viral particles triggered by receptor binding can also facilitate viral entry and uncoating.
Integrins seem to be the "doors" for some viruses to enter the cell (Table 1). The interaction between virus and integrin is important in the viral replication cycle. This interaction brings about membrane permeabilization, fusion, and endocytosis. There are different complex strategies of integrin-dependent viral infection. Integrins can be used either as primary attachment receptors or as co-receptors in the entry process. When virus-integrin interaction occurs, viruses bind to integrin using pattern recognition sequences such as RGD, GRRP, LDV and QAGDV, which are important for natural ligands (16), or interact with unique regions of integrins without necessarily having a recognition sequence.
Table 1. Integrins in viruses entry
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The RGD-binding integrins are among the most promiscuous in the integrin family. Several viruses have been reported to utilize RGD-dependent integrins to initiate infection. Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) uses β1 integrin for infection (8). Field strains of FMDV use at least four integrins αvβ1, αvβ3, αvβ6, αvβ8 as receptors to initiate infection on cultured cells, and integrins are believed to be the receptors used to target epithelial cells in animals (17, 35). Adenovirus has been shown to interact with αvβ3, αvβ5, and αvβ1 integrins via a high-affinity arginine-glycineaspartate (RGD) domain present in the penton bases of the viral capsids (14). Both human parechovirus type 1 and coxsackievirus A9 can use αvβ3 and αvβ1 (33). In addition, αvβ3 and α5β1 have been shown to be receptors of the Barty strain of echovirus type 9 and adenovirus, respectively. Integrins have also been demonstrated as receptors for rotaviruses and papillomaviruses.
Some virus-integrin interactions, however, are independent of RGD motif. Cytomegalovirus can interact with integrin via a highly conserved disintegrin-like domain (10). Hantaan virus, which causes severe respiratory disease in human, has also been reported to use integrin α3β3 for infection, but this interaction seems to be independent of the RGD motif (7). AAV2 lacks the RGD motif, but uses integrin αvβ5 as a coreceptor for cell entry. A recent study demonstrated that a highly conserved domain that contains an asparagine-glycinearginine (NGR) motif on the VP3 domain of the AAV2 could bind integrin α5β1 with moderate affinity, thus mediating AAV2 infection in human embryonic kidney 293 cells (1). Increasing evidences also support the hypothesis that bacteriophages (bacterial viruses) use a cellular receptor β3 integrin for their attachment to eukaryotic cells (12). For example, in T4 phages, there are 55 copies of the KGD motif in the head corner protein; therefore, phages could bind cells that express β3 subunit (platelets, monocytes, some lymphocytes and some neoplastic cells) and downregulate activities of those cells by inhibiting integrin functions (12).