Lu Wuxun, Wan Yanmin, Ma Fangrui, Johnson R Paul, Li Qingsheng
School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
PLoS One. 2017 Mar 23;12(3):e0173929. doi: 10.1371/journal.pone.0173929. eCollection 2017.
The live attenuated vaccine (LAV) SIVmac239Δnef (SIVΔnef) confers the best protection among all the vaccine modalities tested in rhesus macaque model of HIV-1 infection. This vaccine has a unique feature of time-dependent protection: macaques are not protected at 3-5 weeks post vaccination (WPV), whereas immune protection emerges between 15 and 20 WPV. Although the exact mechanisms of the time-dependent protection remain incompletely understood, studies suggested that both cellular and humoral immunities contribute to this time-dependent protection. To further elucidate the mechanisms of protection induced by SIVΔnef, we longitudinally compared the global gene expression profiles of SIV Gag-CM9+ CD8+ (Gag-specific CD8+) T cells from peripheral blood of Mamu-A*01+ rhesus macaques at 3 and 20 WPV using rhesus microarray. We found that gene expression profiles of Gag-specific CD8+ T cells at 20 WPV are qualitatively different from those at 3 WPV. At 20 WPV, the most significant transcriptional changes of Gag-specific CD8+ T cells were genes involved in TCR signaling, differentiation and maturation toward central memory cells, with increased expression of CCR7, TCRα, TCRβ, CD28 and decreased expression of CTLA-4, IFN-γ, RANTES, granzyme A and B. Our study suggests that a higher quality of SIV-specific CD8+ T cells elicited by SIVΔnef over time contributes to the maturation of time-dependent protection.
减毒活疫苗（LAV）SIVmac239Δnef（SIVΔnef）在恒河猴HIV-1感染模型中测试的所有疫苗形式中提供了最佳保护。这种疫苗具有时间依赖性保护的独特特征：猕猴在接种疫苗后3-5周（WPV）没有受到保护，而免疫保护在15至20周龄WPV之间出现。尽管时间依赖性保护的确切机制仍不完全清楚，但研究表明，细胞免疫和体液免疫都有助于这种时间依赖性保护。为了进一步阐明SIVΔnef诱导的保护机制，我们使用恒河猴微阵列纵向比较了Mamu-A*01+恒河猴外周血中SIV Gag-CM9+ CD8+（Gag特异性CD8+）T细胞在3周和20周龄WPV时的整体基因表达谱。我们发现，20周龄WPV时Gag特异性CD8+ T细胞的基因表达谱与3周龄WPV时的定性不同。在20周龄WPV时，Gag特异性CD8+ T细胞最显著的转录变化是参与TCR信号传导、向中央记忆细胞分化和成熟的基因，CCR7、TCRα、TCRβ、CD28表达增加，CTLA-4、IFN-γ、RANTES、颗粒酶A和B表达降低。我们的研究表明，随着时间的推移，SIVΔnef引发的SIV特异性CD8+ T细胞质量更高，有助于时间依赖性保护的成熟。
