DNA vaccine encoding human immunodeficiency virus-1 Gag, targeted to the major histocompatibility complex II compartment by lysosomal-associated membrane protein, elicits enhanced long-term memory response
DNA vaccine encoding human immunodeficiency virus-1 Gag, targeted to the major histocompatibility complex II compartment by lysosomal-associated membrane protein, elicits enhanced long-term memory response
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DOI：
10.1111/j.1365-2567.2004.01823.x
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发表时间：
2004-05-01
期刊：
影响因子：
6.4
通讯作者：
Marques, ETA
中科院分区：
文献类型：
--
作者：
De Arruda, LB;Chikhlikar, PR;Marques, ETA
主要组织相容性复合体II型（MHC II）分子的抗原呈递和CD 4（+）辅助性T细胞的激活对于免疫记忆的产生至关重要。我们以前描述了一种DNA疫苗编码人类免疫缺陷病毒-1 p55 Gag作为嵌合体与溶酶体相关的膜蛋白（LAMP/gag）。LAMP/gag嵌合体蛋白运输到转染细胞的MHC II区室，并且与编码不靶向MHC II区室的天然gag的DNA疫苗相比，增强了免疫应答。我们现在已经研究了免疫小鼠的长期应答，并且显示LAMP/gag DNA疫苗促进持久的B细胞和CD 4（+）和CD 8（+）T细胞记忆应答，并且甚至在免疫后12个月激发有效的Gag特异性CD 8（+）回忆应答。相比之下，由编码非靶向Gag的DNA诱导的免疫应答迅速衰减，并引发非常低或不可检测水平的Gag特异性CD 4（+）和CD 8（+）记忆细胞。用LAMP/ gag DNA的单次引发免疫足以产生T细胞记忆。在用LAMP/gag DNA进行初始初免后，用天然gag DNA或LAMP/gag嵌合体进行加强免疫在引发B-和T-细胞二次应答方面同样有效，结果与加强阶段中CD 8（+）细胞的二次扩增不需要额外的CD 4（+）帮助的观察一致。这些发现强调了将DNA编码的疫苗抗原靶向至MHC II加工区室以诱导长期免疫记忆的重要性。
Antigen presentation by major histocompatibility complex type II (MHC II) molecules and activation of CD4(+) helper T cells are critical for the generation of immunological memory. We previously described a DNA vaccine encoding human immunodeficiency virus-1 p55Gag as a chimera with the lysosome-associated membrane protein (LAMP/gag). The LAMP/gag chimera protein traffics to the MHC II compartment of transfected cells and elicits enhanced immune responses as compared to a DNA vaccine encoding native gag not targeted to the MHC II compartment. We have now investigated the long-term responses of immunized mice and show that the LAMP/gag DNA vaccine promotes long-lasting B cell- and CD4(+) and CD8(+) T-cell memory responses and elicits a potent Gag-specific CD8(+) recall response to challenge with vaccinia virus encoding gag, even II months after immunization. In contrast, the immune responses induced by DNA encoding non-targeted Gag decay rapidly and elicit very low or undetectable levels of Gag-specific CD4(+) and CD8(+) memory cells. A single priming immunization with LAMP/ gag DNA is sufficient to generate T-cell memory. Following this initial priming immunization with LAMP/gag DNA, booster immunizations with native gag DNA or the LAMP/gag chimera are equally efficient in eliciting B- and T-cell secondary responses, results in accordance with observations that secondary expansion of CD8(+) cells in the boost phase does not require additional CD4(+) help. These findings underscore the significance of targeting DNA-encoded vaccine antigens to the MHC II processing compartments for induction of long-term immunological memory.