A dual-purpose hu-mouse model for evaluating SIV and HIV cure strategies

用于评估 SIV 和 HIV 治疗策略的双用途人鼠模型

• 批准号: 10652685
• 负责人: Ramesh Akkina
• 金额: $ 64.39万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652685
• 关键词: 2' -deoxyadenosine; Acquired Immunodeficiency Syndrome; Agonist; Animal Model; Animals; Anti-Retroviral Agents; Biological Models; Biological Products; CD4 Positive T Lymphocytes; Capsid; Caring; Cercocebus atys; Chronic; Data; Evaluation; Evolution; Future; Generations; Gold; Growth; HIV; HIV Infections; HIV-1; HIV-2; Housing; Human; Hybrids; Immune system; Infection; Integrase Inhibitors; Kinetics; Mediating; Modeling; Monitor; Mus; Pan Genus; Pathogenesis; Pharmaceutical Preparations; Play; Research; Reverse Transcriptase Inhibitors; Role; SIV; Savings; System; TLR7 gene; Tenofovir; Testing; Time; Transplantation; Viral; Viral Load result; Viremia; Virus; Virus Latency; Work; chronic infection; combinatorial; cost; drug efficacy; drug testing; efficacy testing; humanized mouse; in vitro testing; in vivo; in vivo Model; in vivo evaluation; inhibitor; medical specialties; mouse model; neutralizing antibody; nonhuman primate; novel therapeutics; progenitor; prophylactic; simian human immunodeficiency virus; therapeutic evaluation; therapeutically effective; transmission process

Project Summary/Abstract: Due to their proven track record in HIV research, NHPs will continue to play a major role into the foreseeable future in HIV cure research. However, the wider use of NHPs is somewhat restrictive due to their high cost and limited supply. In this regard, a small animal model that can serve as a preliminary in vivo screen for the initial evaluation of promising, in vitro-tested, new drugs prior to their evaluation in SIV infected NHPs would be of great benefit in saving time, and in helping to formulate more informed studies. If this same animal model could also allow for the testing of drugs against HIV directly, it would serve two major purposes i. e., the simultaneous ability to test drugs active against both HIV and SIV. In our ongoing work on SIV progenitor viral evolution into HIV, we discovered that humanized mice (hu-mice) transplanted with a human immune system are susceptible to SIVs, namely SIV-chimpanzee (SIVcpz) and SIV-sooty mangabey (SIVsm) that gave rise to HIV-1 and HIV-2, respectively. This forms a basis for our proposed work here to develop and investigate a versatile small animal model that can facilitate the testing of anti-HIV and/or anti-SIV drugs as well as broadly neutralizing antibodies (bNAbs). If successful, this will be a unique model that would benefit both the HIV and SIV research groups involved in cure strategies to streamline their testing pipelines more effectively using the same drugs or biologics on two different viruses within the same animal model. Our specific aims are: Aim 1: Evaluate the humanized mouse model for productive and chronic infection with frequently used SIVs and SHIVs in AIDS research such as SIVmac251, SHIVSF162P3 and RT-SHIV. Aim 2: Validate the utility of the hu-mouse model for in vivo efficacy testing of new generation ARV drugs against SIV and SHIV viruses, namely, NRTI Tenofovir alafenamide (TAF), Islatravir, (4'-ethynyl-2-fluoro-2’- deoxyadenosine, EFdA), Cabotegravir (CAB), and Lenacapvir (GS-6207) Aim 3: Investigate the hu-mouse model for in vivo efficacy testing of bNAbs against SIV and SHIV viruses: Here will evaluate select HIV bNAbs 10-1074 and 3BNC117 on SHIV viruses and bNAbs against SIV ITS103.01 and ITS90.03 in the hu-mouse system Aim 4: Evaluate viral latency reversal and potential cure strategies on SIV/SHIV viruses in the hu-mouse model system: A select combinatorial approaches that incorporate ARVs, LRAs, TLR agonists, and bNAbs against SIV and SHIV to validate the utility of hu-mice in HIV/SIV cure research.

项目摘要/摘要： 由于其在艾滋病毒研究方面的良好记录，NHP 将在可预见的时间内继续发挥重要作用 然而，由于 NHP 的成本高昂，其广泛使用受到一定限制。 在这方面，可以作为初步体内筛选的小动物模型。 在对 SIV 感染的 NHP 进行评估之前，对有前途的、经过体外测试的新药进行初步评估 对于节省时间并帮助对同一动物进行更明智的研究有很大好处。 模型还可以直接测试抗艾滋病毒药物，它有两个主要目的，即 在我们正在进行的 SIV 祖细胞研究中，我们能够同时测试针对 HIV 和 SIV 的药物。 病毒进化为艾滋病毒，我们发现人源化小鼠（hu-mice）移植了人类免疫系统 系统易受 SIV 感染，即 SIV-chimpanzee (SIVcpz) 和 SIV-sooty mangabey (SIVsm)， 这分别产生了 HIV-1 和 HIV-2，这构成了我们在此提出的开发和研究工作的基础。 研究一种多功能的小动物模型，该模型可以促进抗 HIV 和/或抗 SIV 药物的测试 以及广泛中和抗体（bNAb）如果成功，这将是一个受益匪浅的独特模型。 HIV 和 SIV 研究小组都参与了治疗策略，以进一步简化其检测流程 在同一动物模型中有效地使用相同的药物或生物制剂来治疗两种不同的病毒。 具体目标是： 目标 1：评估常用 SIV 的生产性和慢性感染的人源化小鼠模型 艾滋病研究中的 SHIV，例如 SIVmac251、SHIVSF162P3 和 RT-SHIV。 目标2：验证hu-mouse模型在新一代ARV药物体内药效测试中的实用性 抗 SIV 和 SHIV 病毒，即 NRTI 替诺福韦艾拉酚胺 (TAF)、Islatravir、(4'-乙炔基-2-氟-2'- 脱氧腺苷 (EFdA)、卡博特韦 (CAB) 和 Lenacapvir (GS-6207) 目标 3：研究用于体内 bNAb 抗 SIV 和 SHIV 病毒功效测试的 hu-mouse 模型： 这里将评估针对 SHIV 病毒的选定 HIV bNAb 10-1074 和 3BNC117 以及针对 SIV 的 bNAb hu-mouse系统中的ITS103.01和ITS90.03 目标 4：评估 hu-mouse 中 SIV/SHIV 病毒的病毒潜伏期逆转和潜在治愈策略 模型系统：包含 ARV、LRA、TLR 激动剂和 bNAb 的精选组合方法 对抗 SIV 和 SHIV，以验证 hu-mice 在 HIV/SIV 治疗研究中的效用。