Identification and eradication of HIV tissue reservoirs in a relevant animal mode

在相关动物模式中识别和根除 HIV 组织储存库

• 批准号: 8418632
• 负责人: Binhua Julie Ling
• 金额: $ 75.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418632
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Animals; Antiviral Agents; Blood; Bone Marrow; Brain; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Chinese People; Confocal Microscopy; Data; Detection; Drug Combinations; Evolution; Genetic; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Homing; Human; Imaging Techniques; In Situ Hybridization; Individual; Infection; Infection Control; Integrase Inhibitors; Intestines; Knowledge; Latent Virus; Lead; Lymphoid Tissue; Macaca; Macaca mulatta; Methods; Modeling; Monkeys; Mucous Membrane; Mutation; Patients; Phenotype; Plasma; RNA; Regimen; Research; Residual state; Risk; SIV; Sampling; Site; Sorting - Cell Movement; Speed; Spleen; Staging; Stem cells; System; Technology; Testing; Therapeutic; Time; Tissues; Viral; Viremia; Virus; antiretroviral therapy; combat; design; inhibitor/antagonist; insight; lymph nodes; new therapeutic target; nonhuman primate; novel; novel strategies; novel vaccines; public health relevance; treatment strategy

DESCRIPTION (provided by applicant): Although HIV-infected long-term nonprogressors (LTNP) and those on highly active antiretroviral therapy (HAART) have undetectable virus in blood; it is known that virus persists in yet unknown tissue reservoir(s) in essentially all HIV-infected patients throughout the course of infection. A number of tissue reservoirs have been proposed to harbor HIV-1. However, emerging evidence indicates gut-associated lymphoid tissue (GALT) is the major site of viral persistence and reservoir. However, technical challenges and risks limit progress in adequately defining tissue reservoirs in HIV-infected patients. These reasons mandate an assessment of tissue reservoirs using an animal model. Previously, we established a nonhuman primate model using SIV- infected rhesus macaques of Chinese origin (Ch Rh). We found that SIVmac239 infection in Ch Rh more closely mimics HIV-1 infection than other nonhuman primate models. Further, approximately 1/3 of Ch Rh spontaneously control SIV infection despite residual virus in tissues. Recently, we have discovered that the Ch Rh is the premier animal model for studying reservoirs under HAART. The recent addition of integrase inhibitors to the HIV therapeutic arsenal has demonstrated remarkable suppression when combined with standard HAART. Furthermore, we have found that Ch Rh, when treated with anti-SIV regimens that include integrase inhibitors have maximal suppression (< 30 copies/ml) virus in plasma, a feat that had yet to be achieved in a nonhuman primate model. We now have a unique model that can be utilized to test our hypothesis that the intestinal tract is the greatest reservoir for SIV in spontaneous viral controllers or on HAART, and determine whether novel strategies of treatment lead to eventually eradicate virus from these reservoirs. Here we propose: Aim 1. Identify the cellular and tissue reservoirs in SIV-infected macaques on HAART and those that become elite controllers. Using a novel combination of RT inhibitors and integrase inhibitors we will reduce viremia to <10 RNA copies/ml in plasma of treated NP. We will quantify and compare cellular and tissue reservoirs in the intestinal tract, bone marrow, spleen, and other tissues to determine the major reservoirs, we will also analyze viral mutations and evolution among NP on HAART, without HAART and LTNP to examine their association with viral reservoir and combination antiretroviral therapy. Aim 2. Assess the potential for eradication of virus from infected hosts by combining HAART with supplemental regimens or tissue-targeted strategies in early SIV infection. Novel antiviral strategies continue to emerge for HIV infection, and we will incorporate some of the latest antiviral regimens in the SIV-macaque model. For example, we are currently testing fusion inhibitors in macaques, and these may be combined with the above therapy in an attempt to quantify the decay of cell and tissue reservoirs in macaques on multiple drug combinations. Further, we may design specific strategies to target specific sites using the knowledge gained in Aim1 to successful viral eradication. The proposed research will provide new insights into the mechanisms of HIV persistence and latency, and assess whether eradication may be a feasible goal. Finally, these data may identify useful targets for novel therapeutic or vaccine approaches. )

描述（由申请人提供）：尽管HIV感染的长期无进展者（LTNP）和接受高效抗逆转录病毒治疗（HAART）的患者血液中检测不到病毒;但已知病毒在整个感染过程中持续存在于基本上所有HIV感染患者的未知组织储库中。已经提出了许多组织储库来窝藏HIV-1。然而，新的证据表明肠道相关淋巴组织（GALT）是病毒持续存在和储存的主要部位。然而，技术挑战和风险限制了在艾滋病毒感染患者中充分定义组织储库方面的进展。这些原因要求使用动物模型评估组织储库。在此之前，我们用SIV感染的中国恒河猴（ChRh）建立了一个非人灵长类动物模型.我们发现，SIVmac 239感染Ch Rh更接近模仿HIV-1感染比其他非人灵长类动物模型。此外，尽管组织中残留病毒，但约1/3的Ch Rh自发地控制SIV感染。最近，我们发现Ch Rh是HAART下研究储层的首选动物模型。最近加入的整合酶抑制剂的HIV治疗武器库已证明显着抑制时，与标准HAART。此外，我们发现，当用包括整合酶抑制剂的抗SIV方案治疗时，Ch Rh在血浆中具有最大抑制（< 30拷贝/ml）病毒，这是在非人灵长类动物模型中尚未实现的壮举。我们现在有了一个独特的模型，可以用来检验我们的假设，即肠道是自发病毒控制者或HAART中SIV的最大储存库，并确定新的治疗策略是否最终导致从这些储存库中根除病毒。我们在此提出：目标1。识别接受HAART治疗的SIV感染猕猴的细胞和组织储库以及那些成为精英控制者的猕猴。使用RT抑制剂和整合酶抑制剂的新组合，我们将在治疗的NP的血浆中将病毒血症降低至<10 RNA拷贝/ml。我们将量化和比较肠道、骨髓、脾脏和其他组织中的细胞和组织储库，以确定主要储库，我们还将分析HAART治疗的NP之间的病毒突变和演变，而没有HAART和LTNP，以检查它们与病毒储库和联合抗逆转录病毒治疗的相关性。目标二。在SIV感染早期，评估HAART与补充方案或组织靶向策略相结合根除感染宿主病毒的潜力。新的抗病毒策略不断出现的艾滋病毒感染，我们将在SIV猕猴模型中纳入一些最新的抗病毒治疗方案。例如，我们目前正在猕猴中测试融合抑制剂，并且这些可以与上述疗法组合，以试图量化猕猴中细胞和组织储库在多种药物组合下的衰减。此外，我们可能会设计特定的策略，利用Aim 1中获得的知识靶向特定的位点，以成功根除病毒。这项拟议中的研究将为艾滋病毒的持久性和潜伏期机制提供新的见解，并评估根除艾滋病毒是否是一个可行的目标。最后，这些数据可以确定新的治疗或疫苗方法的有用目标。)