Immune escape driven evolution of HIV-1 probed by circulating recombinant forms

通过循环重组形式探测免疫逃逸驱动的 HIV-1 进化

• 批准号: 391559761
• 负责人: Professor Dr. Daniel Hoffmann, Ph.D.
• 金额: --
• 依托单位: Institute of Virology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391559761?language=en
• 关键词: Immune; escape; driven; evolution; HIV

One of the most important defense mechanisms against the Human Immunodeficiency Virus 1 (HIV-1) is recognition of viral fragments by the Human Leucocyte Antigen (HLA) and cytotoxic T lymphocytes (CTLs), leading to the elimination of infected cells. Unfortunately, this mechanism selects mutants of HIV-1 that can evade CTL response. One known way to generate such mutants is by viral recombination. In some cases these recombinant forms can spread in the host population and become so-called circulating recombinant forms (CRFs). Remarkably, most of the HIV-1 infections in China today are caused by CRFs, which motivates our first hypothesis: The high prevalence of specific CRFs in China can be explained by their ability to efficiently evade CTL response in a host population with a specific background of HLA alleles. Our second, related hypothesis (“non-locality” hypothesis) is that HIV-1 in general cannot evade CTL response by local changes of viral genes, despite the recognition of viral fragments by CTL/HLA being local. If the non-locality hypothesis is valid, we have to expect a fundamental impact of viral recombination on the ability of HIV-1 immune escape, which again we will test with CRFs. To test these two hypotheses we will first collect pairs of HLA alleles and HIV-1 genome sequences from publicly available sources and from additional HLA/HIV-1 analyses in China and Germany. Based on these data we will devise a quantitative computational model that allows for the prediction of the effects of specific mutations in CRFs on viral replication and CTL response. These predictions will then be tested experimentally by cellular assays. The project links molecular causes of viral immune escape to the prevalence of viral strains in host populations with specific genomic backgrounds. This knowledge is also relevant for vaccination strategies involving T cell immunity.

人类免疫缺陷病毒1型(HIV-1)最重要的防御机制之一是由人类白细胞抗原(人类白细胞抗原)和细胞毒性T淋巴细胞(CTL)识别病毒片段，从而清除感染细胞。不幸的是，这种机制选择了可以逃避CTL反应的HIV-1突变体。一种已知的产生这种突变的方法是通过病毒重组。在某些情况下，这些重组形式可以在宿主群体中传播，成为所谓的循环重组形式(CRF)。值得注意的是，今天中国的大多数HIV-1感染是由CRF引起的，这引发了我们的第一个假设：中国体内特异性CRF的高流行率可以通过它们在具有特定HLA等位基因背景的宿主人群中有效地逃避CTL反应来解释。我们的第二个相关假说(非局部性假说)是，HIV-1一般不能通过病毒基因的局部变化来逃避CTL反应，尽管CTL/HL A识别病毒片段是局部的。如果非局部性假设是有效的，我们必须预期病毒重组对HIV-1免疫逃逸能力的根本影响，我们将再次用CRF进行测试。为了验证这两个假设，我们将首先从公开来源和中国和德国的额外的人类白细胞抗原/艾滋病毒-1分析中收集人类白细胞抗原等位基因和艾滋病毒-1基因组序列对。基于这些数据，我们将设计一个定量计算模型，允许预测CRF的特定突变对病毒复制和CTL反应的影响。然后，这些预测将通过细胞分析进行实验验证。该项目将病毒免疫逃逸的分子原因与病毒株在具有特定基因组背景的宿主人群中的流行联系起来。这一知识也与涉及T细胞免疫的疫苗接种策略有关。