Role of gammaherpesvirus lytic replication-associated genes in the establishment

描述(申请人提供)：人类伽马疱疹病毒感染与多种类型的恶性肿瘤的发展有关。这些病毒对免疫功能低下的患者，如感染艾滋病毒的患者，构成了特别大的风险。伽马疱疹病毒在B细胞中建立稳定的终生潜伏感染，提供终生病毒储存库，最终可能导致恶性疾病的发展。我们的长期目标是确定伽马疱疹病毒用来建立B细胞潜伏期的机制，从而阐明开发预防伽马疱疹病毒相关恶性肿瘤的方法的新靶点。我们的方法是使用突变病毒在小鼠伽马疱疹病毒(GammaHV68，MHV68)系统中剖析无法进行裂解复制的潜伏期建立的最早事件。通过比较早期和晚期裂解基因突变的病毒，我们发现裂解复制相关基因产物在B细胞潜伏期的建立中起着令人惊讶的作用。我们推测，这些关键的裂解基因产物对于表观遗传修饰的诱导至关重要，表观遗传修饰对于保留潜伏的病毒表观染色体至关重要。这项建议的目标是定义在B细胞感染后最初几个小时发生的关键分子事件，这些事件最终导致病毒Episome在潜伏期保持稳定。具体地说，我们将定义在B细胞潜伏期建立阶段(目标1)发生的病毒转录和基因组事件，我们将定义建立稳定潜伏期所需的特定晚期裂解基因(目标2)，我们将测试关键裂解基因诱导对B细胞潜伏期建立至关重要的表观遗传修饰的假设。这项拟议的研究应该为了解在伽马疱疹病毒感染B细胞的最早时刻发生的关键分子事件提供重要的新见解。 公共卫生相关性：爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒感染与多种癌症的发展有关，对艾滋病患者和移植受者构成特别重大的风险。这项拟议的研究将检查感染早期发生的事件，以努力对这些病毒建立终身感染的方式有新的见解。这项工作对开发预防或治疗病毒相关癌症的药物具有重要意义。

DESCRIPTION (provided by applicant): Human gammaherpesvirus infection is linked to the development of multiple types of malignancies. These viruses pose a particularly significant risk to immunocompromised patients such as those infected with HIV. Gammaherpesviruses establish stable life-long latent infection in B cells, providing a lifelong reservoir of virus that can eventually contribute to the development of malignant disease. Our long-term goal is to define the mechanisms that gammaherpesviruses use to establish latency in B cells, thereby elucidating new targets for the development of modalities to prevent gammaherpesvirus-associated malignancies. Our approach is to dissect the earliest events of latency establishment using mutant viruses in the murine gammaherpesvirus (gammaHV68, MHV68) system that are unable to undergo lytic replication. By comparing viruses that are mutated in early versus late lytic genes, we have uncovered a surprising role for lytic replication-associated gene products in the establishment of latency in B cells. We hypothesize that these key lytic gene products are critical for the induction of epigenetic modifications that are critical for retention of latent viral episomes. The goals of this proposal are to define the critical molecular events that occur in the earliest hours following B cell infection that ultimately result in stable maintenance of the viral episome during latency. Specifically, we will define the viral transcriptional and genomic events that occur during the establishment phase of B cell latency (Aim 1), we will define the specific late lytic gene that is required for the establishment of stable latency (Aim 2), and we will test the hypothesis that the crucial lytic gene induces epigenetic modifications that are critical for latency establishment in B cells. The proposed studies should provide significant new insight into the critical molecular events that occur during the earliest moments of gammaherpesvirus infection of B cells. PUBLIC HEALTH RELEVANCE: Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus infections are linked to the development of numerous types of cancers, and pose a particularly significant risk to AIDS patients and transplant recipients. The proposed research will examine the events that occur in the earliest stages of infection in an effort to gain new insight into the means by which these viruses establish lifelong infections. This work has important implications for the development of drugs to prevent or treat virus-associated cancers.