Develop a therapeutic vaccine approach by removing viral immune evasion

通过消除病毒免疫逃避来开发治疗性疫苗方法

• 批准号: 9256451
• 负责人: REN SUN
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256451
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Attenuated; Biological; Cells; Cessation of life; Complement; Data; Development; Disease; Evolution; Excision; Foundations; Future; Genes; Goals; Growth; HIV; Herpesviridae; Highly Active Antiretroviral Therapy; Human; Human Herpesvirus 4; Human Herpesvirus 8; IFNAR1 gene; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologic Surveillance; Immunologics; In Vitro; Incidence; Individual; Infection; Innate Immune Response; Interferon Type I; Interferons; Knowledge; Lead; Life; Malignant Neoplasms; Measures; Modeling; Mus; Mutate; Natural Immunity; Oral cavity; Patients; Primates; Production; Proteins; Research Proposals; Rodent; Signal Transduction; System; Testing; Therapeutic; Vaccination; Vaccines; Viral; Viral Genes; Viral Physiology; Viral Proteins; Viral Vaccines; Virus; Virus Inactivation; Wing; base; chemotherapy; cytokine; gammaherpesvirus; immunogenic; in vivo; in vivo Model; long term memory; mutant; novel; preclinical study; pressure; prevent; public health relevance; recombinant virus; reconstitution; response; targeted treatment; therapeutic vaccine; type I interferon receptor; vaccine candidate; viral fitness

DESCRIPTION (provided by applicant): Persistent infections of human gamma-herpesviruses, Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), are associated with several malignancies, which frequently develop in immunodeficiency virus (HIV)-infected AIDS patients and often found in their oral cavities. Through co-evolution with hosts, herpesviruses have acquired many strategies to counteract various aspects of the type interferon (IFN) responses, strongly indicating a powerful selective pressure from type I IFNs on the virus to antagonize it for successful infection. Type I IFNs are not only the major anti-viral effector of innate immunity but also important for the development of long-term memory adaptive responses. The overall hypothesis is that the ability to evade the type I IFN response is critical for effective viral growth in a host and that removal f the anti-IFN ability from the virus leads to a highly attenuated but immunogenic virus suitable for vaccination. To test the hypothesis, the following specific aims will be pursued: 1) to elucidate the mechanisms by which the viral genes inhibit type I IFN signaling, 2) to determine the biological significance of anti-IFN genes in vitro and in vivo, and 3) to test a rational therapeutc vaccine strategy by selective inactivation of viral immune evasion genes. The long-term goal is to develop strategies for preventing and treating cancers associated with persistent infections of KSHV and EBV. Accomplishment of the above aims, which is an important step towards achievement of the long-term goal, will demonstrate the feasibility of the therapeutic vaccine approach and establish a foundation for future pre-clinical studies in the KSHV primate model. Moreover, elucidating the anti-IFN function of a group of conserved viral proteins may reveal potential targets for therapeutic measures.

描述（由申请方提供）：人γ-疱疹病毒、EB病毒（EBV或HHV-4）和卡波西肉瘤相关疱疹病毒（KSHV或HHV-8）的持续感染与几种恶性肿瘤相关，这些恶性肿瘤常发生在免疫缺陷病毒（HIV）感染的AIDS患者中，并常在其口腔中发现。通过与宿主的共同进化，疱疹病毒已经获得了许多策略来抵消干扰素（IFN）型应答的各个方面，这强烈表明I型IFN对病毒具有强大的选择性压力，以拮抗其成功感染。I型干扰素不仅是先天免疫的主要抗病毒效应物，而且对于长期记忆适应性反应的发展也很重要。总的假设是逃避I型IFN应答的能力对于宿主中的有效病毒生长是关键的，并且从病毒中去除抗IFN能力导致高度减毒但免疫原性的病毒，其适用于 预防针为了验证这一假设，将追求以下具体目标：1）阐明病毒基因抑制I型IFN信号传导的机制，2）确定抗IFN基因在体外和体内的生物学意义，和3）通过选择性灭活病毒免疫逃避基因来测试合理的治疗性疫苗策略。长期目标是制定预防和治疗与KSHV和EBV持续感染相关的癌症的策略。上述目标的实现是实现长期目标的重要一步，将证明治疗性疫苗方法的可行性，并为KSHV灵长类动物模型的未来临床前研究奠定基础。此外，阐明一组保守的病毒蛋白的抗IFN功能可能揭示治疗措施的潜在目标。