Optimization of immunogen is crucial for induction of effective T-cell responses in the development of a human immunodeficiency virus (HIV) vaccine. Conventional T-cell-based vaccines have been designed to induce virus-specific CD4+ T as well as CD8+ T cells. However, it has been indicated that induction of HIV-specific CD4+ T cells, preferential targets for HIV infection, by vaccination may be detrimental and accelerate viral replication after HIV exposure. In the present study, we present a novel immunogen to selectively induce CD8+ T cells but not CD4+ T cells targeting viral antigens. The immunogen, CaV11, was constructed by tandem connection of overlapping 11-mer peptides spanning simian immunodeficiency virus (SIV) Gag capsid (CA) and Vif. Prime-boost immunization with DNA and Sendai virus (SeV) vectors expressing CaV11 efficiently induced Gag/Vif-specific CD8+ T-cell responses with inefficient Gag/Vif-specific CD4+ T-cell induction in rhesus macaques (n = 6). None of the macaques exhibited the enhancement of acute viral replication after an intravenous high-dose SIV challenge, which was observed in those immunized with DNA and SeV expressing the whole Gag protein in our previous study. Set point viral control postinfection was associated with SeV-specific CD4+ T-cell responses postimmunization, suggesting contribution of SeV-specific helper responses to effective Gag/Vif-specific CD8+ T-cell induction by vaccination. This immunogen design could be a promising method for selective induction of effective anti-HIV CD8+ T-cell responses.IMPORTANCE Induction of effective CD8+ T-cell responses is an important HIV vaccine strategy. Several promising vaccine delivery tools have been developed, and immunogen optimization is now crucial for effective T-cell induction. Conventional immunogens have been designed to induce virus-specific CD4+ T cells as well as CD8+ T cells, but induction of virus-specific CD4+ T cells that are preferential targets for HIV infection could enhance acute HIV proliferation. Here, we designed a novel immunogen to induce HIV-specific CD8+ T cells without HIV-specific CD4+ T-cell induction but with non-HIV antigen-specific CD4+ T-cell help. Our analysis in a macaque AIDS model showed that our immunogen can efficiently elicit effective CD8+ T but not CD4+ T cells targeting viral antigens, resulting in no enhancement of acute viral replication after virus exposure. This immunogen design, also applicable for other currently developed immunogens, could be a promising method for selective induction of effective anti-HIV CD8+ T-cell responses.

中文翻译：

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一种新型免疫原，选择性地靶向靶向免疫缺陷病毒抗原的CD8 + T细胞而不是CD4 + T细胞。

免疫原的优化对于人类免疫缺陷病毒（HIV）疫苗开发中诱导有效T细胞反应至关重要。已经设计了常规的基于T细胞的疫苗，以诱导病毒特异性CD4 + T以及CD8 + T细胞。但是，已经表明，通过疫苗诱导诱导HIV特异性CD4 + T细胞（HIV感染的优先靶标）可能有害，并在HIV暴露后加速病毒复制。在本研究中，我们提出了一种新颖的免疫原，可以选择性地诱导靶向病毒抗原的CD8 + T细胞，而不诱导CD4 + T细胞。通过串联跨越猿猴免疫缺陷病毒（SIV）Gag衣壳（CA）和Vif的11-mer重叠肽串联构建免疫原CaV11。用表达CaV11的DNA和仙台病毒（SeV）载体进行初免-加强免疫，可有效诱导恒河猴猕猴中Gag / Vif特异性CD8 + T细胞的诱导，而Gag / Vif特异性CD4 + T细胞诱导的效率低（n = 6）。静脉内大剂量SIV攻击后，猕猴没有一个显示出增强的急性病毒复制，这在我们先前的研究中观察到了用表达整个Gag蛋白的DNA和SeV免疫的猕猴。设定点病毒控制后感染与免疫后SeV特异性CD4 + T细胞反应相关，表明疫苗接种后SeV特异性辅助反应对有效的Gag / Vif特异性CD8 + T细胞诱导的贡献。这种免疫原设计可能是一种有希望的方法，用于选择性诱导有效的抗HIV CD8 + T细胞反应。重要事项有效的CD8 + T细胞反应的诱导是一项重要的HIV疫苗策略。已经开发了几种有前途的疫苗输送工具，而免疫原优化对于有效诱导T细胞至关重要。已经设计了常规免疫原来诱导病毒特异性CD4 + T细胞以及CD8 + T细胞，但是诱导作为HIV感染优先靶标的病毒特异性CD4 + T细胞可以增强急性HIV扩散。在这里，我们设计了一种新颖的免疫原，可以诱导HIV特异性CD8 + T细胞，而无需HIV特异性CD4 + T细胞诱导，但是具有非HIV抗原特异性CD4 + T细胞帮助。我们在猕猴AIDS模型中进行的分析表明，我们的免疫原可以有效地引发针对病毒抗原的有效CD8 + T细胞，而不是CD4 + T细胞，导致病毒暴露后急性病毒复制没有增强。这种免疫原设计，也适用于其他当前开发的免疫原，可能是选择性诱导有效的抗HIV CD8 + T细胞反应的有前途的方法。