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

众所周知，HIV-1可以通过选择靶区域内的序列变异来逃避病毒特异性细胞免疫应答。编码保护性HLA I类等位基因（包括HLA B27和B57）的个体的细胞免疫应答优先靶向p24 Gag衣壳保守区域内的表位。尽管病毒经常逃避细胞免疫应答，但在这些个体中维持对病毒复制的控制。在这里，我们建议测试这样一个新假设：HIV-1衣壳内免疫驱动的逃逸突变调节衣壳稳定性并增强细胞质受体对病毒寡核苷酸的先天免疫感受。这一假设是基于证明拟定研究可行性的强有力的已发表和初步数据的结果，并将在两个研究目标中进行检验：（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感知病毒寡核苷酸的影响。拟议的项目很好地整合在DFG优先计划先天感应和逆转录病毒的限制（SPP 1923），并将极大地受益于该计划内聚集的集体专业知识。这些研究将弥合我们知识中的一个重要空白，将衣壳内的病毒逃逸与细胞免疫压力联系起来，以增强病毒逃逸变体的先天感应和通过宿主限制因子的病毒控制。

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.