Donor-specific anti-HIV/SIV immunity mediated by APOBEC3 enzymes

APOBEC3 酶介导的供体特异性抗 HIV/SIV 免疫

• 批准号: 10800218
• 负责人: Diako Ebrahimi
• 金额: $ 83.35万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800218
• 关键词: APOBEC3F gene; APOCEC3G gene; Animal Model; Asian population; Cercopithecidae; Clinical; Complex; DNA; Data; Defect; Drug resistance; Effectiveness; Enzymes; European; Evolution; Failure; Frequencies; Genes; Genetic Variation; Goals; HIV; HIV Genome; HIV Infections; HIV-1; HIV-1 protease; Haplotypes; Human; Immune; Immune Evasion; Immunity; Knowledge; Lead; Link; Macaca mulatta; Mediating; Messenger RNA; Methods; Modeling; Molecular; Mutate; Mutation; Outcome; Patients; Pattern; Pharmaceutical Preparations; Population; Process; Protease Inhibitor; Proteins; Proviruses; RNA Splicing; Reporting; Role; SIV; Source; Specificity; Techniques; Terminator Codon; Variant; Viral; Viral Physiology; Virus Replication; attenuation; health disparity; human DNA; insight; nonhuman primate

PROJECT SUMMARY Human APOBEC3 enzymes, particularly APOBEC3D, APOBEC3F, APOBEC3G, and stable haplotypes of APOBEC3H, can induce G>A mutations in the HIV-1 genome. Often, these mutations, particularly those inflicted by APOBEC3G, which is a potent anti-HIV enzyme, generate stop codons and lead to HIV-1 inactivation. Studies have shown that APOBEC3 enzymes can also induce sub-lethal levels of mutations that lead to HIV-1 diversification and drug resistance. Mutations inflicted by different APOBEC3 enzymes and/or different variants of the same APOBEC3 enzyme vary substantially in terms of both their extent and sequence context. For example, APOBEC3H haplotype II often induces many G>A mutations. By contrast, APOBEC3H haplotype I, which is mostly expressed in European and Asian populations, induces little/no changes in the HIV-1 genome. Our analysis of all reported HIV-1 sequences from ~37,000 patients show that the extent and pattern of viral hypermutation is highly patient-specific. Additionally, our data indicate that hypermutation patterns are different between human and nonhuman primate models such as rhesus macaque. We hypothesize that variations in both APOBEC3 and HIV-1 genes are responsible for the observed differential hypermutation patterns. Our preliminary data suggest these variations create a complex cascade of patient-specific interactions between HIV- 1 and APOBEC3 enzymes. In support of this hypothesis, we have identified a patient-specific interaction between APOBEC3H and one of the other APOBEC3 enzymes. This interaction is induced by the HIV-1 protease processing of APOBEC3H Haplotype II splice variant SV200. Additionally, we have generated data that point to a significant defect in APOBEC3G mRNA splicing in non-human primates used frequently as HIV-1 models. Furthermore, our data indicate that variations in multiple HIV-1 proteins, not only Vif, contribute to patient-specific hypermutation patterns. We propose to combine computational and experimental techniques to determine the link between these viral and host variations and differential hypermutation profiles.

项目摘要 人APOBEC 3酶，特别是APOBEC 3D、APOBEC 3F、APOBEC 3G和APOBEC 3的稳定单倍型， APOBEC 3 H可以诱导HIV-1基因组中的G>A突变。通常，这些突变，特别是那些 APOBEC 3G是一种有效的抗HIV酶，产生终止密码子并导致HIV-1失活。研究 已经表明，APOBEC 3酶也可以诱导亚致死水平的突变，导致HIV-1 多样化和耐药性。不同APOBEC 3酶和/或不同变体引起的突变 相同APOBEC 3酶的不同的表达在它们的程度和序列背景方面都有很大的不同。为 例如，APOBEC 3 H单倍型II经常诱导许多G>A突变。相比之下，APOBEC 3 H单倍型I， 主要在欧洲和亚洲人群中表达，在HIV-1基因组中诱导很少/不诱导变化。 我们分析了来自约37，000名患者的所有报告的HIV-1序列，结果显示， 超突变是高度患者特异性的。此外，我们的数据表明， 人类和非人类灵长类动物模型如恒河猴之间的差异。我们假设， APOBEC 3和HIV-1基因都是观察到的差异超突变模式的原因。我们 初步数据表明，这些变异在HIV-1和HIV-2之间产生了复杂的患者特异性相互作用， 1和APOBEC 3酶。为了支持这一假设，我们已经确定了患者之间的特定相互作用 APOBEC 3 H和其他APOBEC 3酶之一。这种相互作用是由HIV-1蛋白酶诱导的 APOBEC 3 H单体型II剪接变体SV 200的加工。此外，我们已经生成的数据表明， 在经常用作HIV-1模型的非人灵长类动物中，APOBEC 3G mRNA剪接存在显著缺陷。 此外，我们的数据表明，多种HIV-1蛋白的变异，不仅是Vif，也有助于患者特异性 超突变模式我们建议联合收割机计算和实验技术，以确定 这些病毒和宿主变异之间的联系以及差异性超突变谱。