The strain 68-1 rhesus cytomegalovirus (RhCMV)–based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8 + T cells that recognize epitopes presented by major histocompatibility complex (MHC)–II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II– and/or MHC-Ia–restricted CD8 + T cells do not protect against SIV, it remains unclear whether MHC-E–restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II–restricted component. Using host microRNA (miR)–mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope–targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142–mediated tropism restriction eliminated MHC-E epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-II epitope–targeted response. Inhibition with the endothelial cell–selective miR-126 eliminated MHC-II epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-E epitope–targeted response. Dual miR-142 + miR-126–mediated tropism restriction reverted CD8 + T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8 + T cell responses were generally similar, only the vectors programmed to elicit MHC-E–restricted CD8 + T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

中文翻译：

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骨髓细胞向性使 RhCMV/SIV 疫苗能够实现 MHC-E 限制的 CD8 + T 细胞启动和疫苗功效


基于 68-1 恒河巨细胞病毒 (RhCMV) 株的猿猴免疫缺陷病毒 (SIV) 疫苗可以通过在原发感染早期阻止病毒复制，严格保护恒河猴 (RM) 免受 SIV 攻击。该疫苗可引发非常规的 SIV 特异性 CD8 + T 细胞识别主要组织相容性复合体 (MHC)–II 和 MHC-E（而不是 MHC-Ia）呈现的表位。尽管 RhCMV/SIV 疫苗基于仅引发 MHC-II 和/或 MHC-Ia 限制性 CD8 的菌株+ T 细胞不能预防 SIV，目前尚不清楚 MHC-E 限制性 T 细胞是否直接负责保护作用，以及这些反应是否可以与 MHC-II 限制性成分分开。利用宿主 microRNA (miR) 介导的载体向性限制，我们发现 MHC-II 和 MHC-E 表位靶向反应的引发取决于 RM 中不同非重叠细胞类型的载体感染。用 miR-142 介导的向性限制选择性抑制骨髓细胞中的 RhCMV 感染，消除了 MHC-E 表位靶向的 CD8 + T 细胞启动，产生专门针对 MHC-II 表位的反应。内皮细胞选择性 miR-126 的抑制消除了 MHC-II 表位靶向的 CD8 + T 细胞启动，产生专门针对 MHC-E 表位的反应。双 miR-142 + miR-126 介导的向性限制恢复 CD8 + T 细胞响应传统的 MHC-Ia 表位靶向。 尽管这些 CD8 的大小和分化状态+ T 细胞反应大体相似，只是载体被编程为引发 MHC-E 限制性 CD8 + T 细胞反应提供了针对 SIV 攻击的保护，直接证明了这些反应在 RhCMV/SIV 疫苗功效中的重要作用。