Consequences of CTL-mediated immune pressure for HIV-1 capsid stability and innate sensing

CTL 介导的免疫压力对 HIV-1 衣壳稳定性和先天感知的影响

• 批准号: 318290718
• 负责人: Professor Dr. Marcus Altfeld
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318290718?language=en
• 关键词: Consequences; CTL; mediated; immune; pressure

It is well established that HIV-1 can evade virus-specific cellular immune responses by selecting for sequence variations within targeted regions. Cellular immune responses in individuals encoding for protective HLA class I alleles, including HLA B27 and B57, preferentially target epitopes within conserved regions of p24 Gag capsid. Despite frequent viral escape from cellular immune responses, control of viral replication is maintained in these individuals. Here we propose to test the novel hypothesis that immune-driven escape mutations within HIV-1 capsid modulate capsid stability and enhance innate immune sensing of viral oligonucleotides by cytoplasmatic receptors. This hypothesis is based on the results of strong published and preliminary data demonstrating the feasibility of the proposed studies, and will be tested in two research objectives: (1) to determine the impact of CTL-driven viral escape mutations within HIV-1 capsids on capsid stability; (2) to assess the consequences of immune-modulated capsid stability for sensing of viral oligonucleotides by cytoplasmatic receptors. The proposed project is well integrated within the DFG Priority Programme Innate Sensing and Restriction of Retroviruses (SPP 1923), and will tremendously benefit from the collective expertise assembled within the Programme. These studies will bridge an important gap in our knowledge by linking viral escape within capsid from cellular immune pressure to enhanced innate sensing of viral escape variants and viral control through host restriction factors.

众所周知，HIV-1可以通过选择靶区内的序列变异来逃避病毒特异性的细胞免疫反应。编码保护性HLAI类等位基因(包括HLAB27和B57)的个体的细胞免疫反应优先针对p24 Gag衣壳保守区域内的表位。尽管病毒经常从细胞免疫反应中逃脱，但这些人仍能控制病毒复制。在这里，我们建议检验这一新的假设，即HIV-1衣壳内免疫驱动的逃逸突变调节衣壳的稳定性，并通过细胞质受体增强对病毒寡核苷酸的天然免疫感知。这一假说基于大量已发表的初步数据，证明了拟议研究的可行性，并将在两个研究目标中进行验证：(1)确定HIV-1衣壳内CTL驱动的病毒逃逸突变对衣壳稳定性的影响；(2)评估免疫调节衣壳稳定性对细胞质受体检测病毒寡核苷酸的影响。拟议的项目与DFG先天感知和限制逆转录病毒优先方案(SPP 1923)很好地结合在一起，并将极大地受益于该方案内汇集的集体专门知识。这些研究将通过将衣壳内的病毒逃脱细胞免疫压力与增强对病毒逃逸变体的先天感觉以及通过宿主限制因子控制病毒联系起来，弥合我们知识中的一个重要缺口。