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: 8932592
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932592
• 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 response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologic Surveillance; In Vitro; Incidence; Individual; Infection; Interferon Type I; Interferons; Knowledge; Lead; Life; Malignant Neoplasms; Maps; 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 Proteins; Viral Vaccines; Virus; Virus Inactivation; Wing; Work; base; chemotherapy; cytokine; fitness; gammaherpesvirus; immunogenic; in vivo; in vivo Model; long term memory; mutant; novel; preclinical study; pressure; prevent; public health relevance; recombinant virus; reconstitution; response; therapeutic target; therapeutic vaccine; type I interferon receptor; vaccine candidate

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（由申请人提供）：人类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有关，这些恶性肿瘤经常发生在免疫缺陷病毒（HIV）感染的艾滋病患者中，通常在他们的口腔中发现。通过与宿主的共同进化，疱疹病毒获得了许多策略来对抗干扰素（IFN）反应的各个方面，这强烈表明I型干扰素对病毒有强大的选择性压力来对抗它以成功感染。I型干扰素不仅是先天免疫的主要抗病毒效应物，而且对长期记忆适应性反应的发展也很重要。总体假设是，逃避I型IFN反应的能力对于病毒在宿主中的有效生长至关重要，并且从病毒中去除抗IFN的能力导致高度减毒但免疫原性的病毒适合于