αVβ5 integrin:: a co-receptor for adeno-associated virus type 2 infection
αVβ5 integrin:: a co-receptor for adeno-associated virus type 2 infection
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DOI：
10.1038/4768
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发表时间：
1999-01-01
期刊：
影响因子：
82.9
通讯作者：
Samulski, RJ
中科院分区：
文献类型：
--
作者：
Summerford, C;Bartlett, JS;Samulski, RJ
了解病毒进入的主要步骤对于预防已知病毒病原体感染的策略以及确定使用病毒载体有效传递基因的参数具有重要意义。最近，对于腺病毒和单纯疱疹病毒，分别确定了病毒感染的两步过程，即病毒与主要受体(柯萨奇病毒腺病毒受体和硫酸乙酰肝素蛋白多糖)的结合以及随后由辅助受体(αV整合素和HSV)介导的病毒进入(1-4)。硫酸乙酰肝素蛋白多糖是二型腺相关病毒(AAV-2)的主要附着受体。5)。在这里，我们确定了αVβ5整合素在有效的AAV感染中发挥了作用。使用螯合剂EDTA破坏整合素功能的实验导致AAV感染的相应减少，这与整合素介导感染的可能性一致。病毒对纯化的质膜蛋白和免疫沉淀的整合素β5亚基的重叠实验表明，AAV与αVβ5整合素的β5亚基直接结合。表达αVβ5整合素的遗传性细胞对AAV感染的易感性增加，证明了这种整合素在AAV感染中的生物学作用。最后，病毒结合和内化研究表明，αVβ5整合素不是AAV-2的主要附着受体，而是参与促进病毒内化。这项研究支持了αVβ5整合素作为AAV-2病毒粒子的辅助受体的观点，并应该对AAV载体在人类基因治疗中的使用产生实质性的影响。
Understanding the primary steps of viral entry can have important implications for strategies to prevent infection of known viral pathogens as well as determining parameters for efficient gene delivery using viral vectors. Recently, a two-step process for viral infection involving attachment of virus to a primary receptor (coxsackievirus adenovirus receptor and heparan sulfate proteoglycan) and subsequent mediation of virus entry by a coreceptor (alpha V integrins and HVEM) has been determined for both adenovirus and HSV, respectively(1-4). Heparan sulfate proteoglycan serves as a primary attachment receptor for adenoassociated virus type 2 (AAV-2)(ref. 5). Here we determined that alpha V beta 5 integrin plays a part in efficient AAV infection. Experiments using the chelating agent EDTA to disrupt integrin function resulted in a corresponding decrease in AAV infection, consistent with the possibility that integrin mediates infection. Viral overlay experiments on purified plasma membrane proteins as well as immunoprecipitated integrin beta 5 subunit demonstrated that AAV directly associates with the beta 5 subunit of alpha V beta 5 integrin. Genetically defined cells expressing alpha V beta 5 integrin showed increased susceptibility to AAV infection, demonstrating a biological role of this integrin in AAV infection. Finally, viral binding and internalization studies indicate that alpha V beta 5 integrin is: not a primary attachment receptor for AAV-2, bur is instead involved in facilitating virus internalization. This study supports the idea that alpha V beta 5 integrin serves as a co;receptor for AAV-2 virions, and should have a substantial effect on the use of AAV vectors in human gene therapy.