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: 8309218
• 负责人: LUBBERTUS C MULDER
• 金额: $ 21.19万
• 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/8309218
• 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.

描述（由申请人提供）：与一般人群相比，HIV-1 AIDS 的特点是肿瘤发生率明显更高。尽管其中一些被描述为艾滋病定义的恶性肿瘤的病因是已知的，但艾滋病非定义恶性肿瘤的病因仍然不确定。尽管抗逆转录病毒治疗非常积极，但非艾滋病定义的恶性肿瘤仍然是 HIV-1 感染者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和恶性肿瘤，因为它解除了对内源性逆转录病毒有效复制的自然抑制。人类内源性逆转录病毒（HERV）占据了人类基因组的很大一部分。在人类进化过程中，基因组不断受到逆转录病毒的入侵，逆转录病毒的复制策略包括整合到生殖系细胞中。这种现象称为内源化，使逆转录病毒能够在垂直和纵向上持续存在。虽然多种宿主机制已保证大多数 HERV 失活，但有令人信服的（尽管是间接的）证据表明内源性逆转录病毒与恶性肿瘤有关。事实上，已经有报道称多种类型的肿瘤以及 HIV-1 感染患者体内都会产生 HERV。 APOBEC3 家族 (A3) 的胞苷脱氨酶是逆转录病毒的有效抑制剂。通过使流出的病毒粒子不具有传染性，A3 分子有可能阻止 HERV 传播和诱导致癌转化。我们假设七种 A3 蛋白和 HERV 之间现有平衡的改变会由于 HERV 复制而导致基因组不稳定。这种保护机制可以被不同的原因抑制，包括 a) HIV Vif，它有效介导一些 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之间表现出拷贝数变异（CNV）的基因组 DNA 片段。据报道，A3 基因座包含至少三个 CNV，其中之一删除了整个 APOBEC3B 开放阅读框。我们的实验策略将测试抑制 A3 家族成员（由 HIV 蛋白 Vif 或 A3B 基因缺失多态性介导）在多大程度上去抑制内源性逆转录病毒，从而为通过插入突变进行致癌转化铺平道路。在我们的第一个具体目标中，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 限制释放对 PBMC 中 HERV 复制的影响。在第二个具体目标中，我们将确定 A3 基因组变异如何影响 HERV 复制。拟议的实验将确定 A3 功能的调节（失调）如何影响 HIV/AIDS 疾病存在和不存在的情况下的基因组稳定性。这些研究可能有助于开发新的恶性肿瘤标志物，并为开发旨在稳定内在免疫防御的新治疗方案打开大门。