Genomic Analysis Reveals Pre- and Postchallenge Differences in a Rhesus Macaque AIDS Vaccine Trial: Insights into Mechanisms of Vaccine Efficacy
Genomic Analysis Reveals Pre- and Postchallenge Differences in a Rhesus Macaque AIDS Vaccine Trial: Insights into Mechanisms of Vaccine Efficacy
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DOI：
10.1128/jvi.01522-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Katze, Michael G.
中科院分区：
文献类型：
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作者：
Palermo, Robert E.;Patterson, L. Jean;Katze, Michael G.
我们利用全血的全局转录谱来识别细胞基因表达的生物学相关变化，以响应替代的艾滋病疫苗策略以及随后在恒河猴疫苗模型中的病毒攻击。在第 0 天（攻击前）、第 14 天（病毒血症峰值）和第 12 周（设定点）从用表达人免疫缺陷病毒 HIVenv89.6P、猿猴免疫缺陷病毒 SIVgag239 或 SIVnef239 的复制型腺病毒 5 型宿主范围 (Ad5hr) 重组病毒单独免疫或与两次肌内加强联合免疫的动物中采集样本。 HIV(89.6P)gp140 Delta CFI 蛋白（L. J. Patterson 等人，Virology 374:322-337, 2008），并且每种治疗均导致在猿猴人类免疫缺陷病毒 SHIV89.6P 攻击后病毒血症得到显着控制（每组六只动物加六只对照）。在最后一次治疗后第 0 天和第 8 周，微阵列图谱显示治疗组之间存在显着的攻击前差异；来自受到最好保护的动物的数据导致了与 B 细胞发育和淋巴细胞存活相关的基因网络的鉴定。在病毒血症高峰期，免疫组的表达谱极其相似，与对照动物的比较反映了效应 T 细胞功能以外的免疫学差异。对于接种疫苗的动物，建议的保护机制包括白介素 27（一种已知可抑制慢病毒复制的细胞因子）的上调，以及补体成分表达的增加，这可能与疫苗诱导的抗体产生协同作用。尽管病毒载量和 CD4(+) T 细胞水平的表型相似，但免疫组在设定点的不同表达谱意味着不同的免疫反应。 gp140增强组的数据为抗体依赖性、细胞介导的病毒控制提供了证据，而仅用复制的Ad5hr重组体免疫的动物甚至在攻击后3个月时也表现出不同的B细胞区室进化。这项研究证明了全血基因表达谱作为艾滋病疫苗试验分析工具的敏感性和辨别力，为体内机制和保护的潜在相关性提供了独特的见解。
We have employed global transcriptional profiling of whole blood to identify biologically relevant changes in cellular gene expression in response to alternative AIDS vaccine strategies with subsequent viral challenge in a rhesus macaque vaccine model. Samples were taken at day 0 (prechallenge), day 14 (peak viremia), and week 12 (set point) from animals immunized with replicating adenovirus type 5 host range (Ad5hr) recombinant viruses expressing human immunodeficiency virus HIVenv89.6P, simian immunodeficiency virus SIVgag239, or SIVnef239 alone or in combination with two intramuscular boosts with HIV(89.6P)gp140 Delta CFI protein (L. J. Patterson et al., Virology 374:322-337, 2008), and each treatment resulted in significant control of viremia following simian-human immunodeficiency virus SHIV89.6P challenge (six animals per group plus six controls). At day 0, 8 weeks after the last treatment, the microarray profiles revealed significant prechallenge differences between treatment groups; data from the best-protected animals led to identification of a network of genes related to B cell development and lymphocyte survival. At peak viremia, expression profiles of the immunized groups were extremely similar, and comparisons to control animals reflected immunological differences other than effector T cell functions. Suggested protective mechanisms for vaccinated animals included upregulation of interleukin-27, a cytokine known to inhibit lentivirus replication, and increased expression of complement components, which may synergize with vaccine-induced antibodies. Divergent expression profiles at set point for the immunized groups implied distinct immunological responses despite phenotypic similarities in viral load and CD4(+) T cell levels. Data for the gp140-boosted group provided evidence for antibody-dependent, cell-mediated viral control, whereas animals immunized with only the replicating Ad5hr recombinants exhibited a different evolution of the B cell compartment even at 3 months postchallenge. This study demonstrates the sensitivity and discrimination of gene expression profiling of whole blood as an analytical tool in AIDS vaccine trials, providing unique insights into in vivo mechanisms and potential correlates of protection.