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的特征是肿瘤发生率显著较高。虽然对于这些恶性肿瘤中的一些，被描述为艾滋病定义，原因是已知的，艾滋病非定义恶性肿瘤的病因仍然不确定。尽管有高度有效的抗逆转录病毒治疗，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，我们建议测试的假设，HIV-1感染导致基因组的不稳定性和恶性肿瘤，因为它解除了内源性逆转录病毒的生产性复制的自然抑制。人内源性逆转录病毒（HERV）占据人类基因组的显著部分。在人类进化过程中，基因组一直处于逆转录病毒的不断入侵之下，逆转录病毒的复制策略包括整合到生殖系细胞中。这种现象被称为内源化，允许逆转录病毒在垂直和纵向上永久存在。虽然有几种宿主机制保证了大多数HERV的失活，但有令人信服的证据表明，内源性逆转录病毒与恶性肿瘤有关。事实上，在几种类型的肿瘤以及HIV-1感染的患者中已经报道了HERV的产生。APOBEC 3家族的胞苷脱氨酶（A3）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感染性，A3分子可能阻止HERV扩散和诱导致癌转化。我们假设，改变现有的平衡之间的七个A3蛋白和HERV导致基因组不稳定性，由于生产性HERV复制。这种保护机制可以被不同的原因抑制，包括a）HIV Vif，其有效地介导几种A3分子的降解，B）A3基因座的基因组结构变异。结构性基因组变异是指个体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，其中一个去除了整个APOBEC 3B开放阅读框。我们的实验策略将测试A3家族成员的抑制（由HIV蛋白Vif或A3 B基因缺失多态性介导）在多大程度上解除内源性逆转录病毒的抑制，从而为通过插入诱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感染的分子基础。我们将测试Vif介导的A3限制的释放对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。拟议的实验将建立如何（dys）调节A3功能影响基因组的稳定性，在没有和艾滋病毒/艾滋病疾病的存在。这些研究可能有助于开发恶性肿瘤的新标志物，并为开发旨在稳定内在免疫防御的新治疗方案打开大门。