可移植的元素可能会增强HIV-1精英控制者的抗病毒抵抗力
Manvendra Singh1,2, Sabrina M Leddy1, Luis Pedro Iñiguez3
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
bioRxiv : the preprint server for biology
|January 3, 2024
概括
携带HIV-1的精英控制者 (EC) 显示出明显的CD4+T细胞基因表达,包括可移植元素 (TE). 通过KRAB指 (KZNF) 蛋白减少抑制可能会增强对HIV-1的自然抵抗力.
科学领域:
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
- 病毒学 病毒学
背景情况:
- 精英控制者 (EC) 占HIV-1感染者的<0.5%,尽管具有复制能力的病毒储存库,但在没有抗逆转录病毒疗法的情况下保持不可检测的病毒载量.
- 虽然研究了ECs的CD4+T细胞转录组,但可移植元素 (TE) 的作用及其在HIV-1控制中的调控活性仍然未被探索.
- 试管婴儿可以影响对病原体的免疫反应,这表明它可能在ECs中观察到的自然耐药性中发挥作用.
研究的目的:
- 研究HIV-1精英控制者的CD4+T细胞转录组内TEs的表达和调节活性.
- 探讨TE监管活动有助于ECs的自然抗性特征的假设.
- 分析多omics数据,以了解与其他HIV-1患者组和健康对照组相比,ECs的独特分子概况.
主要方法:
- 从EC,健康对照,治疗患者和病毒进展者中对现有多种OMIC数据进行了转移元素 (TE) 中心分析.
- 利用转录组和逆转录组数据来比较不同组的基因表达特征.
- 根据染色质可访问性和基因表达模式,分析TE目录和抗病毒因素,将EC分类为不同的集群.
主要成果:
- ECs的CD4+T细胞转录组和逆转录组与健康对照,治疗患者和病毒进展者有显著的区别,尽管ECs表现出转录组异质性.
- 确定了四个不同的EC集群,每个都有独特的TE和抗病毒因子配置文件,其特点是可变的染色质可访问性和表达.
- 在EC中观察到免疫调节TEs的差异表达,与染色质可访问性正相关,与KRAB指 (KZNF) 抑制体表达负相关.
结论:
- 该EC表型可能部分是由TE衍生的cis-regulatory元素的减少KZNF蛋白抑制,增强抗病毒基因表达和自然HIV-1耐药性驱动的.
- 在EC的CD4+T细胞转录组中存在显著的异质性,包括可变的TE表达和KZNF控制器水平.
- 了解这种异质性对于破译精英控制器中自然HIV-1控制的机制至关重要.
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