A Macaque Model to Study HIV-1 RT Antiviral Therapy and

研究 HIV-1 RT 抗病毒治疗的猕猴模型

• 批准号: 7338599
• 负责人: vineet n kewalramani
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338599
• 关键词: Macaque; Model; Study; HIV; RT

We have developed an HIV-1/SIV chimeric virus (RT-SHIVmne) that is susceptible to nonnucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs are important antiviral agents used to treat HIV-1 infection in patients; however, SIVs are naturally resistant to NNRTIs. We elected to use a pathogenic isolate of SIVmne as the basis for constructing the SHIV. SIVmne infects pigtail macaque CD4+ T cells and monocytes/macrophages, cells that could be significant reservoirs for persistent virus replication. RT-SHIVmne replaces the SIV RT coding region with the RT coding region from HIV-1. Our in vitro studies indicate that RT-SHIVmne is appropriately sensitive to NNRTIs used to treat HIV-1-infected patients and generates the same resistance mutations when grown in the presence of NNRTIs. RT-SHIVmne replication has been tested in pigtail macaques. High, persistent viral loads correlate to a gradual decline in CD4+ T cells and mortality with 1-1.5 years of infection. Significantly, we have also demonstrated that an NRTI/NNRTI cocktail, commonly used to treat HIV-1 patients, is highly effective in suppressing virus replication in this model. In a majority of treated animals, RT-SHIVmne can not be detected in the blood plasma after several weeks of therapy. Nonetheless, when treatment is stopped, virus rebounds to pre-therapy levels indicating there are persistent reservoirs. We are now using this model to understand two questions that are difficult to study clinically because of ethical or sampling constraints. We are evaluating the effect of frequent treatment interruptions on the evolution of antiviral resistance. We are also seeking the tissue source of RT-SHIVmne reservoirs that persist during therapy.

我们已经开发了一种HIV-1/SIV嵌合病毒（RT-SHIVMNE），该病毒易受非核苷逆转录酶抑制剂（NNRTIS）的影响。 NNRTI是用于治疗患者HIV-1感染的重要抗病毒剂。但是，SIV天然对NNRTI具有抗性。我们选择使用Sivmne的致病性分离株作为构建SHIV的基础。 Sivmne感染了辫子猕猴CD4+ T细胞和单核细胞/巨噬细胞，这些细胞可能是持续病毒复制的重要储存池。 RT-Shivmne用HIV-1的RT编码区代替SIV RT编码区域。我们的体外研究表明，RT-Shivmne对用于治疗HIV-1感染患者的NNRTI适当敏感，并在nnrtis存在下生长时会产生相同的耐药性突变。 RT-Shivmne复制已在辫子猕猴中测试。高，持续的病毒载量与CD4+ T细胞的逐渐下降和死亡率逐渐下降，并感染1 - 1。5年。值得注意的是，我们还证明，通常用于治疗HIV-1患者的NRTI/NNRTI鸡尾酒在抑制该模型中的病毒复制方面非常有效。在大多数治疗的动物中，几周后无法在血浆中检测到RT-Shivmne。尽管如此，当停止治疗时，病毒会反弹到疗法前水平，表明存在持续的储层。现在，我们正在使用此模型来理解两个由于道德或抽样限制而难以在临床上研究的问题。我们正在评估频繁治疗中断对抗病毒抗性进化的影响。我们还在寻求在治疗过程中持续存在的RT-Shivmne储层的组织来源。