Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation:: Potential of vhs- HSV vectors for dendritic cell-mediated immunotherapy
Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation:: Potential of vhs- HSV vectors for dendritic cell-mediated immunotherapy
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DOI：
10.1128/jvi.77.6.3768-3776.2003
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发表时间：
2003-03-01
影响因子：
5.4
通讯作者：
Coffin, RS
中科院分区：
文献类型：
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作者：
Samady, L;Costigliola, E;Coffin, RS
单纯疱疹病毒(HSV)能有效感染树突状细胞(DC)，但复制最少。因此，HSV似乎已经进化出进入DC的能力，尽管它们不允许病毒生长。这为单纯疱疹病毒向树突状细胞运送基因用于疫苗接种提供了潜在的效用，也表明单纯疱疹病毒的生命周期通常包括树突状细胞感染。然而，感染HSV的DC通常在感染后失去激活的能力(M.Salio，M.Celia，M.Suter和A.Lanzavecchia，EU.J.免疫。29：3245-3253,1999；M.Kruse，O.Rosorius，F.Kratzer，G.Stelz，C.Kuhnt，G.Schuler，J.Hauber，和A.Steinkasserer，J.Virol。74：7127-7136,2000)。我们报道，为了使DC在HSV感染后保持激活的能力，必须删除病毒粒子宿主关闭蛋白(VHS)。VHS通常作用于破坏允许细胞中信使核糖核酸的稳定，有利于HSV蛋白的产生。我们发现，它在DC的失活过程中也起着关键作用，因此很可能对病毒的免疫逃避起着重要作用。在这里，VHS有望在个人感染HSV的早期阶段防止DC激活，减少细胞免疫反应的诱导，从而在病毒潜伏和重新激活的重复周期中防止病毒清除。基于这一信息，已构建了VHS缺失的复制不能HSV载体，该载体允许激活DC并诱导特异性T细胞对递送抗原的反应。这些反应比通过与重组蛋白孵育而负载抗原的DC更大。
Herpes simplex virus (HSV) infects dendritic cells (DC) efficiently but with minimal replication. HSV, therefore, appears to have evolved the ability to enter DC even though they are nonpermissive for virus growth. This provides a potential utility for HSV in delivering genes to DC for vaccination purposes and also suggests that the life cycle of HSV usually includes the infection of DC. However, DC infected with HSV usually lose the ability to become activated following infection (M. Salio, M. Celia, M. Suter, and A. Lanzavecchia, Eur. J. Immunol. 29:3245-3253, 1999; M. Kruse, O. Rosorius, F. Kratzer, G. Stelz, C. Kuhnt, G. Schuler, J. Hauber, and A. Steinkasserer, J. Virol. 74:7127-7136, 2000). We report that for DC to retain the ability to become activated following HSV infection, the virion host shutoff protein (vhs) must be deleted. vhs usually functions to destabilize mRNA in favor of the production of HSV proteins in permissive cells. We have found that it also plays a key role in the inactivation of DC and is therefore likely to be important for immune evasion by the virus. Here, vhs would be anticipated to prevent DC activation in the early stages of infection of an individual with HSV, reducing the induction of cellular immune responses and thus preventing virus clearance during repeated cycles of virus latency and reactivation. Based on this information, replication-incompetent HSV vectors with vhs deleted which allow activation of DC and the induction of specific T-cell responses to delivered antigens have been constructed. These responses are greater than if DC are loaded with antigen by incubation with recombinant protein.