HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells.
HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells.
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DOI：
10.1016/j.ymthe.2016.12.004
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发表时间：
2017-02-01
期刊：
影响因子：
--
通讯作者：
Hanke T
中科院分区：
文献类型：
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作者：
Wee EG;Ondondo B;Berglund P;Archer J;McMichael AJ;Baltimore D;Ter Meulen JH;Hanke T
为了有效对抗1型艾滋病毒（HIV-1），疫苗诱导的T细胞必须选择性地靶向表位，这些表位在功能上是保守的（存在于大多数当前循环和再激活的HIV-1毒株中），同时是有益的（对其反应与更好的临床状态和控制HIV-1复制相关），并且在暴露于病毒后迅速达到保护频率。使用病毒载体疫苗的异源启动-增强方案是目前最有希望的疫苗策略；然而，诱导强健的长期记忆仍然具有挑战性。为此，慢病毒载体由于其低炎症性而诱导高频率的记忆细胞，而通常只诱导低抗载体免疫反应。本文描述了新型候选疫苗ZVex的构建。tHIVconsv1和ZVex。tHIVconsv2，基于整合缺陷慢病毒载体平台，优先转导人类树突状细胞，表达具有高全局HIV-1匹配的保守区T细胞免疫原的二价镶嵌。这两种花叶疫苗都具有单独的免疫原性。当与黑猩猩腺病毒和/或痘病毒修饰的安卡拉牛痘病毒（MVA）疫苗一起以异源启动-增强方案施用于BALB/c和远交种的CD1-Swiss小鼠时，它们诱导了超过6000个T细胞/106个脾细胞的中位频率，这些细胞具有多功能、广泛特异性和交叉反应性。这些结果支持进一步发展这一疫苗概念。Wee等人结合了一种新型慢病毒载体，其特点是增加了树突状细胞的安全性和高效靶向/转导，并具有与全球HIV-1变体高度匹配的HIV-1免疫原。他们证明了诱导有效的、广泛特异性的小鼠CD8+ T细胞，与目前临床开发中的领先方案相当并兼容。
To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/106 splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept. Wee et al. combined a novel lentiviral vector characterized by increased safety and efficient targeting/transduction of dendritic cells with HIV-1 immunogens of uniquely high match to global HIV-1 variants. They demonstrate induction of potent, broadly specific murine CD8+ T cells comparable to and compatible with currently leading regimens in clinical development.