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apobec3酶，尤其是apobec3d，apobec3f，apobec3g和稳定的单倍型 APOBEC3H可以在HIV-1基因组中诱导G> A突变。通常，这些突变，尤其是那些造成的突变 由APOBEC3G（一种有效的抗HIV酶）生成终止密码子并导致HIV-1失活。研究 已经表明，apobec3酶还可以诱导导致HIV-1的突变水平 多样化和耐药性。由不同的APOBEC3酶和/或不同变体产生的突变 同一apobec3酶在其范围和序列上下文方面都有很大差异。为了 例如，APOBEC3H单倍型II通常会诱导许多G> A突变。相比之下，apobec3h单倍型I， 这主要在欧洲和亚洲人群中表达，在HIV-1基因组中几乎没有/无变化。 我们对约37,000名患者的所有报告的HIV-1序列的分析表明，病毒的程度和模式 超名是高度患者特异性的。此外，我们的数据表明超伪标模式不同 在人类和非人类灵长类动物模型（如恒河猴）之间。我们假设这种变化 APOBEC3和HIV-1基因均导致观察到的差异性超称模式。我们的 初步数据表明，这些变化在HIV-之间产生了复杂的患者特异性相互作用的级联 1和apobec3酶。为了支持这一假设，我们确定了患者特定的相互作用 APOBEC3H和其他APOBEC3酶之一。这种相互作用是由HIV-1蛋白酶诱导的 APOBEC3H单倍型II剪接变体SV200的处理。此外，我们生成的数据指向 非人类灵长类动物中APOBEC3G mRNA剪接的显着缺陷经常用作HIV-1模型。 此外，我们的数据表明，多种HIV-1蛋白的变化，不仅有助于患者特异性 超名模式。我们建议将计算和实验技术结合起来，以确定 这些病毒和宿主变化与差异超伪造曲线之间的联系。