HIV Env conserved element DNA vaccine alters immunodominance in macaques.
HIV Env conserved element DNA vaccine alters immunodominance in macaques.
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DOI：
10.1080/21645515.2017.1339852
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发表时间：
2017-12-02
影响因子：
4.8
通讯作者：
Felber BK
中科院分区：
文献类型：
--
作者：
Hu X;Valentin A;Rosati M;Manocheewa S;Alicea C;Chowdhury B;Bear J;Broderick KE;Sardesai NY;Gall SL;Mullins JI;Pavlakis GN;Felber BK
序列多样性和免疫优势是设计有效的艾滋病毒疫苗的主要障碍。HIV Env是一种高度糖基化的蛋白质，由“保守”区和“可变区”组成。后者包含免疫优势表位，这些表位经常被免疫系统靶向，导致产生免疫逃逸变异体。这项工作描述了HIV Env中的12个区域，这些区域在已知的HIV M组序列(Env CE)中高度保守，并且在全长表达Env的DNA疫苗免疫猕猴中免疫原性较差。产生了编码12Env CE的两个版本的质粒，每个CE相差0-5aa，以最大限度地包含通常检测到的变体。与全长env DNA疫苗相比，这两种env CE DNA的组合免疫猕猴可以诱导出强大而持久的细胞免疫应答，其中相当一部分CD8+T细胞具有细胞毒表型(颗粒酶B+和CD107a+)。虽然在产生对CE的主要反应方面效率不高，但用完整的env DNA疫苗增强Env CE DNA免疫的猕猴，有效地增强了原有的免疫，增加了细胞反应的幅度、广度和细胞毒性。精细定位显示，12个CE中有7个激发了T细胞反应。Env CE DNA还能诱导能够识别全长Env的体液反应。因此，Env CE质粒能够诱导对Env高度保守区域的持久反应，这些区域在Env疫苗接种后经常缺失或在免疫上处于劣势。这些修饰的抗原可用作预防性和治疗性艾滋病毒疫苗。
Sequence diversity and immunodominance are major obstacles in the design of an effective vaccine against HIV. HIV Env is a highly-glycosylated protein composed of ‘conserved’ and ‘variable’ regions. The latter contains immunodominant epitopes that are frequently targeted by the immune system resulting in the generation of immune escape variants. This work describes 12 regions in HIV Env that are highly conserved throughout the known HIV M Group sequences (Env CE), and are poorly immunogenic in macaques vaccinated with full-length Env expressing DNA vaccines. Two versions of plasmids encoding the 12 Env CE were generated, differing by 0–5 AA per CE to maximize the inclusion of commonly detected variants. In contrast to the full-length env DNA vaccine, vaccination of macaques with a combination of these 2 Env CE DNA induced robust, durable cellular immune responses with a significant fraction of CD8+ T cells with cytotoxic phenotype (Granzyme B+ and CD107a+). Although inefficient in generating primary responses to the CE, boosting of the Env CE DNA primed macaques with the intact env DNA vaccine potently augmented pre-existing immunity, increasing magnitude, breadth and cytotoxicity of the cellular responses. Fine mapping showed that 7 of the 12 CE elicited T cell responses. Env CE DNA also induced humoral responses able to recognize the full-length Env. Env CE plasmids are therefore capable of inducing durable responses to highly conserved regions of Env that are frequently absent after Env vaccination or immunologically subdominant. These modified antigens are candidates for use as prophylactic and therapeutic HIV vaccines.
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影响因子：
15.3
作者：
Harari, Alexandre;Bart, Pierre-Alexandre;Stoehr, Wolfgang;Tapia, Gonzalo;Garcia, Miguel;Medjitna-Rais, Emmanuelle;Burnet, Severine;Cellerai, Cristina;Erlwein, Otto;Barber, Tristan;Moog, Christiane;Liljestrom, Peter;Wagner, Ralf;Wolf, Hans;Kraehenbuhl, Jean-Pierre;Esteban, Mariano;Heeney, Jonathan;Frachette, Marie-Joelle;Tartaglia, James;McCormack, Sheena;Babiker, Abdel;Weber, Jonathan;Pantaleo, Giuseppe
通讯作者：
Pantaleo, Giuseppe
影响因子：
7.8
作者：
Felber BK;Valentin A;Rosati M;Bergamaschi C;Pavlakis GN
通讯作者：
Pavlakis GN
影响因子：
82.9
作者：
Fischer, Will;Perkins, Simon;Korber, Bette T.
通讯作者：
Korber, Bette T.
影响因子：
--
作者：
Kopycinski, Jakub;Cheeseman, Hannah;Vasan, Sandhya
通讯作者：
Vasan, Sandhya
影响因子：
3.7
作者：
Kulkarni V;Valentin A;Rosati M;Alicea C;Singh AK;Jalah R;Broderick KE;Sardesai NY;Le Gall S;Mothe B;Brander C;Rolland M;Mullins JI;Pavlakis GN;Felber BK
通讯作者：
Felber BK