Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system
Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system
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DOI：
10.1128/jvi.77.4.2400-2409.2003
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发表时间：
2003-02-01
影响因子：
5.4
通讯作者：
Johnson, PR
中科院分区：
文献类型：
--
作者：
Evans, DT;Chen, LM;Johnson, PR
几乎所有人类免疫缺陷病毒（HIV）感染都是通过粘膜获得的，肠道相关淋巴组织是早期病毒复制的重要场所。因此，旨在引发病毒特异性细胞毒性 T 淋巴细胞 (CTL) 反应（归巢于粘膜区室）的疫苗策略可能在预防或遏制 HIV 感染方面特别有效。沙门氏菌 III 型分泌系统已被证明是刺激小鼠粘膜 CTL 反应的有效方法。因此，我们测试了表达与 III 型分泌的 SopE 蛋白融合的猿猴免疫缺陷病毒 (SIV) Gag 蛋白片段的鼠伤寒沙门氏菌和伤寒沙门氏菌血清变种的 DeltaphoP-phoQ 减毒株是否能够在恒河猴中引发病毒特异性 CTL 反应。 Mamu-A*01(+) 猕猴接种了三剂口服重组沙门氏菌，然后用表达 SIV Gag (MVA Gag) 的修饰痘苗病毒安卡拉进行外周加强。每次沙门氏菌给药后，检测到对 Mamu-A*01 Gag(181-189) 表位的瞬时低水平 CTL 反应。用MVA Gag加强后，一致检测到强烈的Gag特异性CTL反应，四聚体染色显示外周血中Gag(181-189)特异性CD8(+) T细胞反应的扩展。每只动物中很大一部分 Gag(181-189) 特异性 T 细胞群也表达肠道归巢受体 α4β7。此外，在从结肠分离的淋巴细胞中检测到Gag(181-189)特异性CD8(+)T细胞。然而，尽管有这些反应，沙门氏菌引发/MVA 增强的动物在用 SIVmac239 进行直肠攻击后并未表现出对病毒复制的控制得到改善。尽管如此，这项研究表明，在灵长类动物模型中，III 型沙门氏菌分泌系统的粘膜启动有可能引导 SIV 特异性细胞免疫反应至胃肠粘膜。
Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested DeltaphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01(+) macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag(181-189) epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag(181-189)-specific CD8(+) T-cell responses in peripheral blood. A significant percentage of the Gag(181-189)-specific T-cell population in each animal also expressed the intestinal homing receptor alpha4beta7. Additionally, Gag(181-189)-specific CD8(+) T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.