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，在可预见的未来，国家卫生政策将继续发挥重要作用。 艾滋病治疗研究的未来。然而，由于成本高，NHP的广泛使用在某种程度上受到限制。 和有限的供应。在这方面，一种可以作为初步体内筛查的小动物模型 在对SIV感染的NHP进行评估之前，有希望的体外测试新药的初步评估将 在节省时间和帮助制定更有见地的研究方面大有裨益。如果这只动物 该模型还可以直接测试抗艾滋病毒药物，它将有两个主要目的，即， 同时测试抗艾滋病毒和SIV的药物的能力。在我们正在进行的关于SIV前体的工作中 病毒进化成HIV后，我们发现人源化的小鼠(Hu小鼠)移植了一种人类免疫 系统对SIV敏感，即SIV-黑猩猩(SIVcpz)和SIV-煤烟芒果(SIVsm) 分别导致了HIV-1和HIV-2的产生。这构成了我们在这里提议的工作的基础，以开发和 研究一种通用的小动物模型，该模型可以促进抗HIV和/或抗SIV药物的测试 以及广谱中和抗体(BNAbs)。如果成功，这将是一种独特的模式，将使 艾滋病毒和SIV研究小组都参与了治愈战略，以更好地简化他们的检测管道 在同一动物模型中对两种不同的病毒有效地使用相同的药物或生物制品。我们的 具体目标是： 目的1：评价经常使用SIV的人源化小鼠生殖力和慢性感染模型 SIVmac251、SHIVSF162P3、RT-SHIV等在艾滋病研究中的应用。 目的2：验证人-鼠模型在新一代抗逆转录病毒药物体内疗效测试中的应用 抗SIV和SIV病毒，即NRTI替诺福韦丙氨酰胺(TAF)，伊沙拉韦，(4‘-乙炔基-2-氟-2’- 脱氧腺苷(EFdA)、卡替格韦(CAB)和来那普韦(GS-6207) 目的3：探讨抗SIV和SIV病毒bNAbs体内药效检测的人-鼠模型： 这里将评估精选的HIV bNAbs 10-1074和3BNC117对SIV病毒的作用和bNAbs对SIV的作用 人-鼠系统中的ITS103.01和ITS90.03 目的4：评价人小鼠体内SIV/SIV病毒潜伏期逆转及可能的治疗策略 模型系统：包括ARV、LRAs、TLR激动剂和bNAbs的精选组合方法 针对SIV和SIV，验证HU-小鼠在HIV/SIV治愈研究中的应用。