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

项目概要/摘要： 由于其在艾滋病毒研究方面的良好记录，国家卫生保健人员在可预见的未来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，更广泛地使用国家卫生方案受到一定的限制 有限的供应。在这方面，可以使用小动物模型作为初步的体内筛选， 在对SIV感染的NHP进行评价之前，对有前景的体外试验新药进行初步评价， 这将大大有助于节省时间，并有助于制定更知情的研究。如果这只动物 该模型还可以直接测试抗艾滋病毒的药物，它将用于两个主要目的：例如， 同时测试抗HIV和SIV药物的能力。在我们正在进行的SIV祖细胞研究中， 病毒进化成艾滋病毒，我们发现，人源化小鼠（hu-mice）移植了人类免疫 系统易受SIV感染，即SIV-黑猩猩（SIVcpz）和SIV-黑白眉猴（SIVsm）， 分别产生了HIV-1和HIV-2。这构成了我们在这里拟议开展的工作的基础， 研究一种通用的小动物模型，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，这将是一个独特的模式， 艾滋病毒和SIV研究小组都参与了治疗策略，以简化他们的测试流程， 在相同的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剂。我们 具体目标是： 目的1：评价常用SIV的生产性和慢性感染的人源化小鼠模型 和艾滋病研究中的SHIV，如SIVmac 251、SHIVSF 162 P3和RT-SHIV。 目的2：验证新一代抗逆转录病毒药物体内药效试验的hu-小鼠模型的实用性 针对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）和来那普韦（GS-6207） 目的3：研究用于bNAb针对SIV和SHIV病毒的体内功效测试的hu-mouse模型： 本文将评价选择的HIV bNAb 10-1074和3BNC 117对SHIV病毒的作用以及针对SIV的bNAb hu-小鼠系统中的ITS103.01和ITS90.03 目的4：评估病毒潜伏逆转和对SIV/SHIV病毒在hu小鼠中的潜在治疗策略 模型系统：一种精选的组合方法，包括ARV、LRA、TLR激动剂和bNAb 针对SIV和SHIV的抗HIV/SIV的抗体，以验证hu-mice在HIV/SIV治愈研究中的效用。

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.