Generation of Genotypically Diverse R5 SHIVs as Tools in HIV-1 Vaccine Research

生成基因型多样化的 R5 SHIV 作为 HIV-1 疫苗研究的工具

• 批准号: 8845512
• 负责人: CECILIA C CHENG-MAYER
• 金额: $ 86.54万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845512
• 关键词: AIDS Vaccines; AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Animal Model; Animals; Antibodies; Antigens; Antiviral Agents; Basic Science; Binding; Biological Models; Blood; Bone Marrow; CCR5 gene; CD8B1 gene; Cells; Chronic; Clinical; Clinical Research; Country; Deposition; Development; Disease; Encephalitis; Generations; Genetic; Giant Cells; Goals; HIV; HIV vaccine; HIV-1; Health; Human; Immune response; Immune system; Immunologic Deficiency Syndromes; Infection; Investigation; Letters; Macaca; Macaca mulatta; Medicine; Modeling; Molecular Cloning; Monitor; Monkeys; Monoclonal Antibody R24; Pathogenesis; Pathogenicity; Preclinical Testing; Prevalence; Prevention; Prevention therapy; Process; Prophylactic treatment; Publications; Reagent; Research; Research Personnel; Resources; Serial Passage; Staging; Terminal Disease; Therapeutic; Therapeutic Human Experimentation; Translational Research; Vaccine Design; Vaccine Research; Vaccines; Variant; Viremia; Virus; Virus Diseases; Virus Replication; base; env Glycoproteins; experience; improved; in vivo; neuropathology; nonhuman primate; novel; pandemic disease; pre-clinical; pre-clinical research; repository; research clinical testing; research study; simian human immunodeficiency virus; stem; success; tool; tool development; vaccination strategy; vaccine development; vaccine evaluation; vaccine-induced immunity; web site

DESCRIPTION (provided by applicant): The goal of this R24 application is to generate a panel of reliable pathogenic R5 SHIVs representing globally circulating HIV-1 strains, with emphasis on subtype C and CRF_AE that are fueling the HIV-1 pandemic. We envision that these novel SHIVs which recapitulate the immunopathogenesis of HIV in humans will serve as valuable resources not only as challenge viruses in preclinical nonhuman primate (NHP) studies to determine if vaccine-induced immunity has activities against multiple variants within a single genetic subtype as well as across subtypes, but to improve our understanding on the pathogenesis of the HIV-induced immunodeficiency to advance progress towards treatment, prevention and cure. The proposed project leverages the complementary expertise of Dr. Cheng-Mayer in SHIV models of AIDS and of Dr. Blanchard in nonhuman primate medicine, and builds on our documented experience in generating successful R5 SHIVs in HIV-1 vaccine and pathogenesis studies. In aim 1, we will characterize a recently obtained late-stage SHIVC isolate for its ability to transmit mucosally, maintain chronic viremia durably and induce disease consistently with development of giant cell encephalitis and coreceptor switching. In aim 2, we will construct three additional R5 SHIV molecular clones expressing Envs from transmitter/founder or early infection subtype C and CRF_01AE viruses. We will adapt and improve their replicative capacity in vivo by performing four rapid serial passages in Indian rhesus macaques, the most commonly used monkey species for AIDS research. Development of disease in the late passage macaques will be monitored. In aim 3, we will evaluate the suitability of swarm cell-free viruses recovered from the subtype C and CRF_AE SHIV passage macaques with disease as challenge viruses by assessing their mucosal transmissibility and ability to induce chronic viremia and immunodeficiency. We believe the potential impact of the resources is substantial. Resource applications include: (1) development of tools for AIDS vaccine research in NHPs; (2) development of tools for preclinical pre-exposure prophylaxis (PrEP), therapeutic and cure studies; (3) investigation of the interaction between HIV-1 subtype and the immune system during acute and chronic infection; (4) investigation of the impact of HIV-1 subtype on AIDS pathogenesis. We envision the R5 SHIVs and models generated will guide vaccine design and development, generate new hypotheses and experiments in AIDS pathogenesis to advance basic and translational discovery research, and facilitate preclinical research in HIV prevention, therapeutics and cure.

描述（由申请人提供）：该R24应用程序的目的是生成代表全球循环HIV-1菌株的可靠的致病性R5 SHIV，重点是亚型C和CRF_AE，这助长了HIV-1大流行。我们设想，这些新型的SHIV概括了人类中的HIV免疫病原体，不仅是临床前非人类灵长类动物（NHP）研究中的挑战病毒的宝贵资源，以确定疫苗诱导的免疫力可以确定疫苗对单个遗传亚型的跨性别变化的影响，还可以改善跨越子类型的进步，并在跨越的范围内进行了进步，并且在跨越的理解方面涉及疫苗的发展。治疗，预防和治愈。拟议的项目利用了Cheng-Mayer博士在AIDS和Blanchard博士的非人类灵长类医学模型中的补充专业知识，并建立在我们在HIV-1疫苗和发病机理研究中成功获得成功的R5 SHIV的经验。 在AIM 1中，我们将表征最近获得的后期SHIVC分离株，其能够传播粘液，维持慢性病毒血症持久，并诱发疾病，并始终伴随着巨大的细胞脑炎和肌受感受器转换的发展。在AIM 2中，我们将构建三个R5 SHIV分子克隆，这些克隆来自发射器/创始人或早期感染亚型C和CRF_01AE病毒。我们将通过在印度恒河猕猴中进行四个快速的串行段落，这是最常用的艾滋病研究猴子。将监测猕猴晚期疾病的发展。在AIM 3中，我们将通过评估其通过评估其粘膜的传播性以及诱导慢性病毒性和免疫缺陷的能力来评估从亚型C和CRF_AE SHIV通道作为挑战病毒的无细胞病毒的适用性。 我们认为资源的潜在影响是巨大的。资源应用包括：（1）开发NHP中艾滋病疫苗研究工具； （2）开发用于临床前预防前预防的工具（PREP），治疗和治疗研究； （3）研究急性和慢性感染期间HIV-1亚型与免疫系统之间的相互作用； （4）研究HIV-1亚型对AIDS发病机理的影响。我们设想生成的R5 SHIV和模型将指导疫苗的设计和开发，在AIDS发病机理中产生新的假设和实验，以推动基本和转化的发现研究，并促进HIV预防，治疗和治疗方面的临床前研究。