Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United States.
Front Immunol. 2024 Nov 4;15:1491481. doi: 10.3389/fimmu.2024.1491481. eCollection 2024.
Nonhuman primate (NHP) models employing simian/simian-human immunodeficiency viruses (SIV/SHIVs) played a major role in the study of HIV pathogenesis, latency, and cure studies in a preclinical setting. However, it took many years to arrive at the current effective triple drug ARV regimen against SIV due to the genetic differences with that of HIVs. Since new combinations of drugs will be used in the evolving HIV cure studies, a small animal model would be ideal to determine their efficacy against the commonly used SIVs such as SIVmac239 to triage ineffective drugs prior to their application in NHPs. We recently determined that humanized mice (hu-mice) with a transplanted human immune system are permissive to SIVmac strains in addition to HIVs. Based on this novel finding, here we evaluated the utility of this dual-purpose hu-mouse model to test different ART regimens against SIVmac239. Infected mice showing chronic viremia were treated with a combination anti-retroviral treatment (cART) regimen consisting of emtricitabine/elvitegravir/tenofovir disoproxil fumarate (FTC/EVG/TDF). Full viral suppression was seen for several weeks in SIVmac239-infected and treated mice similar to that seen with HIV-1 BaL virus used as a control. However, viral rebound was eventually observed in SIVmac239 infected mice during the treatment period, suggesting viral escape compared to HIV-1 BaL with which viral suppression was fully sustained. Next, a cART regimen consisting of emtricitabine/bictegravir/tenofovir alafenamide fumarate (FTC/BIC/TAF) was similarly evaluated. Our results showed that this ARV regimen was fully effective in rapidly suppressing both SIVmac239 and HIV-1 BaL. Complete viral suppression was maintained until treatment interruption after which viral loads rebounded. These findings highlight the utility of humanized mice for screening of new combinations of ARV compounds against various SIVs prior to employing them in NHPs. In addition to identifying new effective cART regimens against SIVs, this model would also be amenable to evaluating immunotherapeutic strategies using broadly neutralizing antibodies, LRAs and novel therapeutics in comparative cure studies of SIV and HIV.
非人类灵长类动物（NHP）模型采用猿猴/猿猴人类免疫缺陷病毒（SIV/SHIV）在临床前环境中对 HIV 发病机制、潜伏和治愈研究起到了重要作用。然而，由于与 HIV 的遗传差异，经过多年才得到目前针对 SIV 的有效三联抗逆转录病毒治疗（ARV）方案。由于在不断发展的 HIV 治愈研究中将会使用新的药物组合，一种小动物模型将是理想的，可以确定它们对常用 SIV（如 SIVmac239）的疗效，以便在将其应用于 NHP 之前筛选出无效药物。我们最近发现，移植了人类免疫系统的人源化小鼠（hu-mice）除了 HIV 外，还允许 SIVmac 株感染。基于这一新颖发现，我们在此评估了这种双重用途的 hu-mouse 模型在测试针对 SIVmac239 的不同 ART 方案中的效用。感染 SIVmac239 的慢性病毒血症小鼠用包含恩曲他滨/艾维雷格韦/替诺福韦富马酸酯（FTC/EVG/TDF）的抗逆转录病毒联合治疗（cART）方案进行治疗。与用作对照的 HIV-1 BaL 病毒类似，在 SIVmac239 感染和治疗的小鼠中观察到数周的完全病毒抑制。然而，在治疗期间，最终观察到 SIVmac239 感染的小鼠中病毒反弹，表明与 HIV-1 BaL 相比存在病毒逃逸，而 HIV-1 BaL 则完全维持了病毒抑制。接下来，同样评估了包含恩曲他滨/比克替拉韦/替诺福韦艾拉酚胺富马酸盐（FTC/BIC/TAF）的 cART 方案。我们的结果表明，该 ARV 方案能够迅速有效地抑制 SIVmac239 和 HIV-1 BaL。完全病毒抑制一直持续到治疗中断后病毒载量反弹。这些发现突出了人源化小鼠在将新的 ARV 化合物组合用于 NHP 之前筛选针对各种 SIV 的用途。除了确定针对 SIV 的新有效 cART 方案外，该模型还适用于评估使用广泛中和抗体、LRA 和新型疗法进行 SIV 和 HIV 比较治愈研究的免疫治疗策略。
