Delivery of human immunodeficiency virus vaccine vectors to the intestine induces enhanced mucosal cellular immunity.
Delivery of human immunodeficiency virus vaccine vectors to the intestine induces enhanced mucosal cellular immunity.
复制标题
将人类免疫缺陷病毒疫苗载体递送至肠道可诱导增强的粘膜细胞免疫。
DOI：
10.1128/jvi.00374-09
复制
发表时间：
2009
影响因子：
5.4
通讯作者：
Nabel,GaryJ
中科院分区：
文献类型：
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作者：
Wang,Lingshu;Cheng,Cheng;Ko,Sung-Youl;Kong,Wing-Pui;Kanekiyo,Masaru;Einfeld,David;Schwartz,RichardM;King,CRichter;Gall,JasonGD;Nabel,GaryJ
针对 1 型人类免疫缺陷病毒 (HIV-1) 的有效疫苗可能需要刺激肠粘膜的保护性免疫，而 HIV-1 感染会导致肠粘膜严重的 CD4+T 细胞耗竭。虽然具有复制能力的重组腺病毒 (rAd) 载体可以在复制后刺激腺病毒特异性粘膜免疫，但口服递送编码特定免疫原的复制缺陷型 rAd 载体已被证明具有挑战性。在这项研究中，我们系统地确定了 rAd 载体有效肠道递送的障碍，并确定了诱导有效细胞和体液免疫的位点和策略。 rAd5 载体介导的基因转移对低 pH 缓冲液、胃蛋白酶和胰腺蛋白酶以及细胞外粘蛋白敏感。使用离体器官外植体，我们发现在所有肠段中，回肠和结肠中 rAd5 的转导率最高。直接手术引入回肠后的转基因表达比口服强饲后高 100 倍，rAd5 比 rAd35 或 rAd41 载体显示出更强的效力。编码HIV-1 gp140B的rAd5对回肠的单次免疫刺激了肠道和全身区室中有效的CD8+T细胞反应，并且这些反应通过肌内rAd5加强进一步增强。这些研究表明，通过 rAd5 肠道免疫诱导初次免疫反应以及随后的全身加强会引发有效的抗原特异性肠粘膜反应。
Effective vaccines for human immunodeficiency virus type 1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4+T-cell depletion. While replication-competent recombinant adenovirus (rAd) vectors can stimulate adenovirus-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, we have systematically identified barriers to effective gut delivery of rAd vectors and identified sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low-pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, we found that transduction with rAd5 was highest in the ileum and colon among all intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than after oral gavage, with rAd5 showing greater potency than the rAd35 or the rAd41 vector. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8+T-cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization and subsequent systemic boosting elicits potent antigen-specific gut mucosal responses.
产后发育过程中营养素的利用。
DOI：
--
发表时间：
1966
期刊：
影响因子：
--
作者：
P. Hahn;O. Koldovský
通讯作者：
O. Koldovský