Interaction of ICP34.5 with Beclin 1 Modulates Herpes Simplex Virus Type 1 Pathogenesis through Control of CD4+ T-Cell Responses
Interaction of ICP34.5 with Beclin 1 Modulates Herpes Simplex Virus Type 1 Pathogenesis through Control of CD4+ T-Cell Responses
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DOI：
10.1128/jvi.01676-09
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发表时间：
2009-12-01
影响因子：
5.4
通讯作者：
Ferguson, Thomas A.
中科院分区：
文献类型：
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作者：
Leib, David A.;Alexander, Diane E.;Ferguson, Thomas A.
自噬是宿主对病毒天然免疫和适应性免疫的重要组成部分。它对于细胞内病原体的降解和促进抗原呈递至关重要。单纯疱疹病毒1型（HSV-1）感染诱导自噬反应，但这种反应被HSV-1神经毒力基因产物ICP 34.5拮抗。这部分是由于其通过ICP 34.5的Beclin结合结构域（BBD）与必需的自噬蛋白Beclin 1（Atg 6）相互作用。使用缺乏BBD的重组病毒，我们使用小鼠感染模型研究了发病机制和免疫应答。BBD缺陷型病毒（Delta 68 H）在早期的复制与其标记拯救的对应物（Delta 68 HR）相当，但在角膜感染后的晚期，其从所有组织中清除的速度比Delta 68 HR更快。此外，角膜感染Delta 68 H比Delta 68 HR引起的眼部疾病更少。这些结果表明，Delta 68 H由于其未能控制适应性而不是先天性免疫而被减弱。为了支持这一观点，Delta 68 H刺激了显著更强的CD 4（+）T细胞介导的迟发型超敏反应，并导致HSV特异性CD 4（+）T细胞产生的γ干扰素和白细胞介素-2显著多于Delta 68 HR。总之，这些数据表明ICP 34.5的BBD在排除自噬介导的II类抗原呈递中的作用，从而增强HSV-1的毒力和发病机制。
Autophagy is an important component of host innate and adaptive immunity to viruses. It is critical for the degradation of intracellular pathogens and for promoting antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces an autophagy response, but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5. This is due, in part, to its interaction with the essential autophagy protein Beclin 1 (Atg6) via the Beclin-binding domain (BBD) of ICP34.5. Using a recombinant virus lacking the BBD, we examined pathogenesis and immune responses using mouse models of infection. The BBD-deficient virus (Delta 68H) replicated equivalently to its marker-rescued counterpart (Delta 68HR) at early times but was cleared more rapidly than Delta 68HR from all tissues at late times following corneal infection. In addition, the infection of the cornea with Delta 68H induced less ocular disease than Delta 68HR. These results suggested that Delta 68H was attenuated due to its failure to control adaptive rather than innate immunity. In support of this idea, Delta 68H stimulated a significantly stronger CD4(+) T-cell-mediated delayed-type hypersensitivity response and resulted in significantly more production of gamma interferon and interleukin-2 from HSV-specific CD4(+) T cells than Delta 68HR. Taken together, these data suggest a role for the BBD of ICP34.5 in precluding autophagy-mediated class II antigen presentation, thereby enhancing the virulence and pathogenesis of HSV-1.