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流行，延迟疾病，延长寿命并改变了与HIV相关的神经认知障碍（手）的性质，从明显的痴呆症到认知/运动障碍。抗逆转录病毒药物具有不同的能力，可以渗透到中枢神经系统中。从人类中的HAART治疗中，CNS-PENETRANT HAART是否可以通过减少CNS的病毒复制和CNS炎症来改善中枢神经系统结局，还是矛盾地造成长期CNS损害，因为较高的CNS潜在神经毒性药物较高导致长期CNS损害。我们开发并表征了抗逆转录病毒疗法（CART）的严格SIV SIV猕猴模型，该模型与HIV感染的个体中的HAART非常相似，结合了CNS渗透率较低的抗逆转录病毒药物。该模型的价值是：1）感染了CD4+ T细胞和单核细胞/巨噬细胞，2）在接受HAART处理的猕猴中的组织，包括脑和脾脏避开病毒，在受HIV感染的人中精确建模HAART，3）在血液和淋巴机中与HAHIV相比，在血液和淋巴机中，在HAPHORIAD COMPARE IN IV-INFF中的静息CD4+细胞的数量与HAHIV相比。这些优势证明了该模型在大脑和周围神经系统中研究潜在病毒储存的能力。使用敏感的 单复制测定； SIV DNA水平与未处理的SIV感染的猕猴相媲美，并且大脑的炎症发生了持续的变化。现在，我们建议使用CNS-渗透剂推车（PCART）研究SIV模型，以确定其影响，并将其直接与非CNS-PENETRANT ART（NCART）进行比较，以便1）控制病毒复制和炎症2）减少脑中病毒DNA储层3）3）保留神经元功能的标记。我们还将检查PCART与NCART在停止推车后延长病毒重新激活时间的相对能力。我们的假设是，在减少CSF和CNS中的残留病毒复制，减少大脑中的病毒储量以及由于病毒DNA和残留病毒复制的撤回CRITAID COVINID和延迟的CRAMPAINS和DELACTING INTRAWINS和DELACTING IFENS，并延迟，CNS-渗透剂CART在减少CSF和CNS中的残留病毒复制方面将比非非探针car更有效。但是，CNS渗透剂推车也可能具有神经毒性作用，而CNS和PNS的神经元损伤增加。我们将：1）使用优化的CNS-PENETRANT CART（PCART）与我们的SIV猕猴模型中的非渗透液（NCART）表征和比较血浆和CSF中SIV的衰减动力学；定量和比较PCART与NCART处理的动物中血浆，PBMC，CSF和组织中的残留病毒复制； 2）检查血液和CD4+T细胞中CD4+T细胞和单核细胞中的病毒潜伏期，以及用PCART＆NCART处理的SIV感染猕猴的组织中的巨噬细胞； 3）测量具有PCART和NCART方案的SIV感染猕猴中神经元功能的CN和PNS标记，以评估神经保护和神经毒性； 4）比较PCART与NCART延迟或防止病毒从储层中延迟或防止病毒重新激活的能力，其中包括SIV感染的猕猴中的CNS。