Genome stability function of APOBEC3 retroviral restriction factors

APOBEC3逆转录病毒限制因子的基因组稳定性功能

• 批准号: 8209618
• 负责人: LUBBERTUS C MULDER
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209618
• 关键词: AIDS related cancer; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Cancer Patient; Cause of Death; Cells; Copy Number Polymorphism; Cytidine Deaminase; DNA; Data; Development; Disease; Endogenous Retroviruses; Epigenetic Process; Equilibrium; Etiology; Evolution; Failure; Family; Family member; General Population; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genome Stability; Genomic Instability; Genomics; Germ Cells; Goals; HERVs; HIV; HIV-1; Human; Human Genome; Immune; In Vitro; Incidence; Individual; Infection; Insertional Mutagenesis; Investigation; Lifting; Link; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Oncogenes; Oncogenic; Open Reading Frames; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Plasma; Primates; Production; Proteins; RNA Interference; Reagent; Regulation; Reporting; Research; Retroelements; Retroviridae; Risk; Risk Factors; System; Testing; Variant; Viral Load result; Virion; Work; base; cancer type; immortalized cell; inhibitor/antagonist; insight; malignant breast neoplasm; novel marker; prevent; reconstitution; research study; structural genomics; tumor; vif Gene Products

DESCRIPTION (provided by applicant): HIV-1 AIDS is marked by a significantly higher incidence of tumor development, compared to the general population. Although for some of these malignancies, described as AIDS-defining, the cause is known, the etiology of the AIDS non-defining malignancies remains uncertain. Despite highly active antiretroviral treatments, non-AIDS defining malignancies remain among the leading causes of death in HIV-1 infected individuals. Here we propose to test the hypothesis that HIV-1 infection leads to genomic instability and malignancies because it lifts the natural inhibition on productive replication of endogenous retroviruses. Human endogenous retroviruses (HERVs) occupy a remarkable portion of the human genome. During human evolution the genome has been under constant invasion by retroviruses whose replicative strategy includes integration in the germ-line cells. This phenomenon, known as endogenization, permits the retrovirus to perpetuate itself both vertically and longitudinally. While several host mechanisms have guaranteed the inactivation of most HERVs, there is compelling, albeit circumstantial, evidence implicating endogenous retroviruses in malignancies. HERV production has, indeed, been reported in several types of tumors as well as in HIV-1 infected patients. Cytidine deaminases of the APOBEC3 family (A3) are potent inhibitors of retroviruses. By rendering egressing virions non infectious, A3 molecules potentially prevent HERVs from spreading and inducing oncogenic transformation. We hypothesize that alteration of the existing equilibrium between the seven A3 proteins and HERVs leads to genomic instability due to productive HERV replication. This protective mechanism can be suppressed by different causes, including a) HIV Vif, which efficiently mediates the degradation of several of the A3 molecules, b) genomic structural variation of the A3 locus. Structural genomic variation refers to genomic DNA segments that show copy number variation (CNV) among individuals. The A3 locus has been reported to encompass at least three CNVs, one of which removes the whole APOBEC3B open reading frame. Our experimental strategy will test to what extent suppression of A3 family members (mediated by HIV protein Vif or by A3B genetic deletion polymorphism) de-represses endogenous retroviruses, paving the way to oncogenic transformation via insertional mutagenesis. In our first Specific Aim, we will determine the molecular basis of HIV-1-dependent HERV infectivity. We will test the impact of Vif-mediated release of the A3 restriction on HERV replication in PBMC. In the second Specific Aim we will determine how A3 genomic variation influences HERVs replication. The proposed experiments will establish how (dys)regulation of A3 function affects genome stability in the absence and presence of HIV/AIDS disease. These studies may help develop new markers for malignancies and open doors for the development of new treatment options aimed at stabilizing intrinsic immune defenses. PUBLIC HEALTH RELEVANCE: The goal of this proof of concept study is to test whether intracellular APOBEC3 cytidine deaminases, which efficiently restrict exogenous also contribute to the inhibition of endogenous retroviruses replication. It seeks to understand how interference with the APOBEC3 protection system, by HIV-1 and genetic variation, reactivates these endogenous retroviruses and poses an added risk to genome stability.

描述（由申请人提供）：与普通人群相比，HIV-1 AIDS的特征是肿瘤发育的发生率明显更高。尽管其中一些恶性肿瘤被描述为定义的艾滋病，但已知原因，艾滋病的病因非定义恶性肿瘤仍然不确定。尽管高度活跃的抗逆转录病毒治疗，但定义恶性肿瘤的非辅助药物仍然是HIV-1感染个体死亡的主要原因之一。在这里，我们建议检验以下假设：HIV-1感染会导致基因组不稳定性和恶性肿瘤，因为它可以自然抑制内源性逆转录病毒的生产性复制。人内源性逆转录病毒（HERV）占据了人类基因组的显着部分。在人类进化过程中，基因组一直受到逆转录病毒的持续侵袭，其复制策略包括在细菌细胞中的整合。这种现象被称为内源化，允许逆转录病毒在垂直和纵向上延续自身。尽管几种宿主机制保证了大多数HERV的失活，但仍有引人注目的（尽管有环境，证据）涉及内源性逆转录病毒。确实，已经报道了几种类型的肿瘤以及HIV-1感染患者的HERV产生。 APOBEC3家族的胞苷脱氨酶（A3）是逆转录病毒的有效抑制剂。通过渲染非感染性病毒体的流出，A3分子有可能阻止赫尔维斯扩散和诱导致癌性转化。我们假设七种A3蛋白和HERV之间现有平衡的改变会导致基因组不稳定性，这是由于生产性HERV的复制而导致的。这种保护机制可以通过不同的原因抑制，包括a）HIV VIF，该原因有效地介导了A3分子的几种A3分子的降解，b）A3基因座的基因组结构变异。结构基因组变异是指个体中显示拷贝数变化（CNV）的基因组DNA段。据报道，A3基因座至少包含三个CNV，其中一个删除了整个APOBEC3B开放式阅读框架。我们的实验策略将在多大程度上测试A3家族成员（由HIV蛋白VIF或A3B遗传缺失多态性介导的介导的抑制作用）会消除内源性逆转录病毒，从而通过插入诱变为源源源性转化铺平了道路。在我们的第一个特定目标中，我们将确定HIV-1依赖性HERV感染性的分子基础。我们将测试VIF介导的A3限制对PBMC中HERV复制的影响。在第二个特定目的中，我们将确定A3基因组变异如何影响HERV复制。提出的实验将确定（DYS）在没有HIV/AIDS疾病的情况下（DYS）调节A3功能如何影响基因组稳定性。这些研究可能有助于为恶性肿瘤开发新的标志物，并为开发旨在稳定内在免疫防御能力的新治疗方案开发开门。 公共卫生相关性：该概念证明研究的目的是测试细胞内APOBEC3胞苷脱氨酶是否有效限制外源性也有助于抑制内源性逆转录病毒复制。它试图通过HIV-1和遗传变异来理解对APOBEC3保护系统的干扰，将这些内源性逆转录病毒重新激活，并对基因组稳定性构成增加的风险。