Novel SIV Model of HAND

HAND的新颖SIV模型

• 批准号: 8894623
• 负责人: JANICE E CLEMENTS
• 金额: $ 75.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894623
• 关键词: Animal Model; Animals; Anti-Retroviral Agents; Atazanavir; Biological Assay; Blood; Brain; CD4 Positive T Lymphocytes; Cells; Cerebrospinal Fluid; Cognition Disorders; Cognitive; DNA; Dementia; Disease; Epidemic; HIV; HIV-associated neurocognitive disorder; Highly Active Antiretroviral Therapy; Human; Individual; Inflammation; Inflammatory; Integrase Inhibitors; Kinetics; Latent Virus; Life; Lymphoid Tissue; Macaca; Measures; Modeling; Motor; Nature; Neurons; Outcome; Patients; Penetrance; Penetration; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Plasma; Principal Investigator; Recovery; Regimen; Relative (related person); Residual state; Rest; SIV; Saquinavir; Spinal Cord; Spinal Ganglia; Spleen; Tenofovir; Time; Tissues; Viral; Viral Load result; Virus; Virus Diseases; Virus Latency; Virus Replication; Withdrawal; analog; antiretroviral therapy; base; brain tissue; improved; inflammatory marker; lymph nodes; macrophage; monocyte; motor disorder; neuroprotection; neurotoxic; neurotoxicity; novel; peripheral blood; pinacolyl methylphosphonic acid; prevent; viral DNA

DESCRIPTION (provided by applicant): HAART has dramatically changed the HIV epidemic, delaying disease, prolonging life and altering the nature of HIV-associated neurocognitive disorders (HAND) from overt dementia to cognitive/motor disorders. Antiretroviral drugs have differing capacities to penetrate into the CNS. It is not clear from HAART therapy in humans whether CNS-penetrant HAART improves CNS outcomes by reducing viral replication and inflammation in the CNS or paradoxically contributes to long term CNS damage due to higher CNS levels of potentially neurotoxic drugs. We developed and characterized a rigorous SIV macaque model of combined antiretroviral therapy (cART) that is very similar to HAART in HIV-infected individuals, combining classes of antiretroviral drugs that have low CNS penetrance. The value of this model is: 1) Both CD4+ T cells and monocyte/macrophages are infected, 2) tissues including brain and spleen harbor virus in HAART-treated macaques, accurately modeling HAART in HIV-infected humans, 3) the number of latently infected resting CD4+ cells in blood and lymphoid tissues is comparable to that in HIV-infected patients on HAART. These advantages demonstrate the model's ability to study latent viral reservoirs in brain and the peripheral nervous system. Virus replication in brain is detectable at low levels using a sensitive single copy assay; SIV DNA levels were comparable to untreated SIV-infected macaques, and there were ongoing inflammatory changes in brain. We now propose to study a SIV model using CNS-penetrant cART (pcART) to determine its impact and compare it directly with non-CNS-penetrant ART (ncART) for ability to 1) control viral replication& inflammation 2) reduce viral DNA reservoirs in brain 3) preserve markers of neuronal function. We will also examine the relative ability of pcART versus ncART to prolong time to virus reactivation after stopping cART. Our hypothesis is that CNS-penetrant cART will be more effective than non-penetrant cART in reducing residual viral replication in CSF and CNS, in reducing viral reservoirs in brain, and potentially other tissues due to increased penetration, as measured by viral DNA and residual virus replication, in reducing CNS inflammation, and in delaying virus reactivation upon withdrawal of cART. However, CNS-penetrant cART might also have neurotoxic effects with increased neuronal damage in both CNS and PNS. We will: 1) Characterize and compare decay kinetics of SIV in plasma and CSF using an optimized CNS-penetrant cART (pcART) to non- penetrant cART (ncART) in our SIV macaque model; quantitate and compare residual virus replication in plasma, PBMCs, CSF and tissues in pcART versus ncART-treated animals; 2) Examine viral latency in CD4+T cells and monocytes in blood and CD4+T cells and macrophages in tissues of SIV-infected macaques treated with pcART & ncART; 3) Measure CNS and PNS markers of neuronal function in SIV-infected macaques with pcART & ncART regimens to evaluate neuroprotection and neurotoxicity; 4) Compare ability of pcART versus ncART to delay or prevent reactivation of virus from reservoirs including the CNS in SIV-infected macaques.

描述（由申请人提供）：HAART 极大地改变了 HIV 的流行，延缓了疾病，延长了生命，并改变了 HIV 相关神经认知障碍 (HAND) 的性质，从明显的痴呆转变为认知/运动障碍。抗逆转录病毒药物渗透到中枢神经系统的能力不同。人类HAART治疗尚不清楚中枢神经系统渗透性HAART是否通过减少中枢神经系统中的病毒复制和炎症来改善中枢神经系统结果，或者由于潜在神经毒性药物的中枢神经系统水平较高而导致长期中枢神经系统损伤。我们开发并表征了严格的 SIV 猕猴联合抗逆转录病毒治疗 (cART) 模型，该模型与 HIV 感染者的 HAART 非常相似，结合了中枢神经系统外显率较低的抗逆转录病毒药物类别。该模型的价值在于：1) CD4+ T 细胞和单核细胞/巨噬细胞均被感染，2) 在经过 HAART 治疗的猕猴中，包括大脑和脾脏在内的组织中含有病毒，准确地模拟了 HIV 感染者中的 HAART，3) 潜伏病毒的数量血液和淋巴组织中受感染的静息 CD4+ 细胞与接受 HAART 的 HIV 感染患者相当。这些优势证明了该模型能够研究大脑和周围神经系统中的潜在病毒库。使用敏感的方法可检测到低水平的病毒在大脑中的复制 单拷贝测定； SIV DNA 水平与未经治疗的感染 SIV 的猕猴相当，并且大脑中存在持续的炎症变化。我们现在建议使用 CNS 渗透性 cART (pcART) 研究 SIV 模型，以确定其影响，并将其直接与非 CNS 渗透性 ART (ncART) 进行比较，以了解 1) 控制病毒复制和炎症 2) 减少病毒 DNA 储存的能力大脑 3) 保留神经元功能的标记。我们还将检查 pcART 与 ncART 在停止 cART 后延长病毒重新激活时间的相对能力。我们的假设是，中枢神经系统渗透性 cART 将比非渗透性 cART 更有效地减少脑脊液和中枢神经系统中的残留病毒复制，减少大脑和其他组织中的病毒储存，因为渗透性增加（通过病毒 DNA 和残留病毒来测量）病毒复制，减少中枢神经系统炎症，并在 cART 撤药后延迟病毒重新激活。然而，中枢神经系统渗透性 cART 也可能具有神经毒性作用，增加中枢神经系统和三七总皂甙中的神经元损伤。我们将： 1) 在我们的 SIV 猕猴模型中使用优化的 CNS 渗透性 cART (pcART) 与非渗透性 cART (ncART) 来表征和比较血浆和脑脊液中 SIV 的衰变动力学；定量并比较 pcART 与 ncART 治疗动物血浆、PBMC、CSF 和组织中残留病毒的复制； 2) 检查经pcART & ncART处理的SIV感染的猕猴血液中CD4+T细胞和单核细胞以及组织中CD4+T细胞和巨噬细胞的病毒潜伏期； 3）采用pcART和ncART方案测量SIV感染猕猴神经元功能的CNS和PNS标志物，以评估神经保护和神经毒性； 4) 比较 pcART 与 ncART 在 SIV 感染的猕猴中延迟或防止病毒从储存库（包括中枢神经系统）重新激活的能力。