Induction/Eradication of SIV in an Optimized HAART CNS Macaque Model

虽然HAART对艾滋病的流行有很大的影响，但它不会结束艾滋病的流行;需要的是清除身体的感染，这将需要使用药物进入骨髓，大脑，任何含有潜伏艾滋病毒的组织，并清除或降低这些病毒库，使HAART成为不必要的。抗逆转录病毒药物的设计并不需要动物模型，但动物模型是测试药物诱导潜伏HIV和根除潜伏病毒库的能力的重要临床前步骤。由于这些药物的潜在毒性和未知功效，有效的动物模型对于测试将诱导/根除潜伏HIV的治疗剂以用于临床试验设计是至关重要的。我们在HIV感染者中有一个严格的HAART SIV模型，该模型将外周血和脑脊液（CSF）中的病毒载量降低到无法检测的水平，并在组织、大脑和脾脏中的CD 4 + T细胞和巨噬细胞中存在潜伏病毒。艾滋病毒根除需要HAART，包括CNS渗透性抗逆转录病毒药物（ART），因为大脑是病毒潜伏的部位。我们将使用我们的SIV猕猴使用当前ART药物优化CNS渗透HAART方案，确认药物在组织中达到有效水平，定量CSF和脑中每种抗逆转录病毒药物的水平。使用这种SIV HAART模型，假设单核细胞/巨噬细胞谱系细胞中存在潜伏的病毒储库（除了CD 4 + T细胞），并且可能存在于CD 34+细胞中，并且需要动物模型来识别、定量和表征这些储库。我们假设，通过诱导潜伏感染细胞中的病毒再活化，并通过有效穿透组织（包括脑）的ART阻止病毒生命周期的完成，可以从组织中根除病毒感染。我们将在该SIV模型中表征CD 4 + T细胞、单核细胞、组织巨噬细胞和OD 34+细胞（脑、脾、骨髓、淋巴结、肺和肠）中的潜在储库。一旦血浆中潜伏感染的静息CD 4 + T细胞数量达到稳定水平，我们将在SIV感染的猕猴中用HAART测试诱导/根除药物，定量诱导治疗前后血浆、CSF和脾活检中残留的病毒复制和潜伏感染细胞。我们将检查退出HAART后病毒再激活的时间，成功的诱导/根除治疗可能不会导致病毒再激活。我们将使用这样一个成功的治疗方案来剖析这种诱导/根除方法的分子基础。

While HAART has significantly impacted the AIDS epidemic it will not end the epidemic; the need is to purge the body of infection which will require the use of drugs that reach into bone marrow, brain, any tissue that harbors latent HIV and clear or lower these viral reservoirs to make HAART unnecessary. Animal models were not required for design of antiretroviral drugs, but are an essential preclinical step to test the ability of drugs to induce latent HIV and eradicate latent viral reservoirs. Because of potential toxicity and unknown efficacy of such drugs, an effective animal model is critical for testing of therapeutic agents that will induce/eradicate latent HIV for design of clinical trials. We have a rigorous SIV model of HAART in HIVinfected individuals that reduces viral load in peripheral blood and cerebrospinal fluid (CSF) to undetectable levels and have latent virus in CD4+ T cells and macrophages in tissues, brain and spleen. HIV eradication requires HAART that includes CNS-penetrant antiretrovirals (ARTs) since brain is a site of viral latency. We will optimize a CNS-penetrant HAART regimen using current ART drugs using our SIV macaque, confirming that drugs reach effective levels in tissues quantitating CSF and brain levels of each antiretroviral drug. Using this SIV HAART model, the hypothesis that latent viral reservoirs (in addition to CD4+ T cells) in cells ofthe monocyte/macrophage lineage and potentially in CD34+ cells exist, and that an animal model is required to identify, quantitate and characterize these reservoirs. We hypothesize that viral infection can be eradicated from tissues by inducing virus reactivation from latently infected cells and preventing completion ofthe virus life cycle by ART that effectively penetrate tissues, including brain. We will characterize latent reservoirs in this SIV model in CD4+ T cells, monocytes, tissue macrophages and OD34+ cells (brain, spleen, bone marrow, lymph nodes, lung and gut). We will test induction/eradication drugs in SIV-infected macaques with HAART once the number of latently infected resting CD4+ T cells plateaus in plasma, quantitate residual virus replication and latently infected cells in plasma, CSF and spleen biopsies before and after induction therapy. We will examine the time to virus reactivation after withdrawal from HAART and successful induction/eradication therapy may result in no virus reactivation. We will use such a successful treatment regimen to dissect the molecular basis ofthis induction/eradication approach.