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 申请的目标是生成一组可靠的致病性 R5 SHIV，代表全球流行的 HIV-1 毒株，重点关注助长 HIV-1 大流行的 C 亚型和 CRF_AE。我们设想，这些概括了人类 HIV 免疫发病机制的新型 SHIV 将作为宝贵的资源，不仅作为临床前非人灵长类动物 (NHP) 研究中的挑战病毒，以确定疫苗诱导的免疫是否具有针对单一遗传亚型内的多种变异的活性，例如以及跨亚型，但为了提高我们对艾滋病毒引起的免疫缺陷发病机制的了解，以推动治疗、预防和治愈的进展。拟议的项目利用了 Cheng-Mayer 博士在艾滋病 SHIV 模型方面和 Blanchard 博士在非人类灵长类动物医学方面的互补专业知识，并以我们在 HIV-1 疫苗和发病机制研究中成功生成 R5 SHIV 的记录经验为基础。 在目标 1 中，我们将表征最近获得的晚期 SHIVC 分离株，因为它能够通过粘膜传播、持久维持慢性病毒血症以及与巨细胞脑炎和辅助受体转换的发展一致地诱导疾病。在目标 2 中，我们将构建三个额外的 R5 SHIV 分子克隆，表达来自传播者/创始人或早期感染 C 亚型和 CRF_01AE 病毒的 Envs。我们将通过在印度恒河猴（艾滋病研究中最常用的猴类）中进行四次快速连续传代来适应和提高它们的体内复制能力。将监测晚期猕猴疾病的发展。在目标 3 中，我们将通过评估其粘膜传播性和诱导慢性病毒血症和免疫缺陷的能力，评估从患有疾病的 C 亚型和 CRF_AE SHIV 传代猕猴中回收的群体无细胞病毒作为攻击病毒的适用性。 我们相信这些资源的潜在影响是巨大的。资源应用包括：（1）NHP艾滋病疫苗研究工具开发； (2) 开发临床前暴露前预防（PrEP）、治疗和治愈研究的工具； （3）急、慢性感染过程中HIV-1亚型与免疫系统相互作用的研究； (4)HIV-1亚型对艾滋病发病机制影响的调查。我们预计 R5 SHIV 和生成的模型将指导疫苗设计和开发，产生艾滋病发病机制的新假设和实验，以推进基础和转化发现研究，并促进艾滋病毒预防、治疗和治愈的临床前研究。