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: 8225153
• 负责人: Binhua Julie Ling
• 金额: $ 81.28万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225153
• 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. ) PUBLIC HEALTH RELEVANCE: HIV-1 persistence in infected individuals is the obstacle in curing HIV-1 infection. The proposed research is to use SIV infection in monkeys of Chinese origin as a model to identify cellular and tissue sites that harbor replication competent but latent viruses, and test new potent strategies to eradicate these viruses which could be directed towards the eradication of HIV-1 infection.

描述（由申请人提供）：尽管hiv感染的长期非进展者（LTNP）和接受高活性抗逆转录病毒治疗（HAART）的患者血液中检测不到病毒；众所周知，在几乎所有hiv感染患者的整个感染过程中，病毒持续存在于未知的组织库中。许多组织储存库被认为是HIV-1的避难所。然而，越来越多的证据表明，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，技术上的挑战和风险限制了在充分确定艾滋病毒感染患者的组织库方面取得进展。这些原因要求使用动物模型对组织库进行评估。之前，我们用感染SIV的中国恒河猴（Ch Rh）建立了一个非人灵长类动物模型。我们发现在Rh中的SIVmac239感染比其他非人灵长类动物模型更接近于模仿HIV-1感染。此外，尽管组织中有残留病毒，但约1/3的Rh可自发控制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。最近将整合酶抑制剂添加到HIV治疗武器库中，与标准HAART联合使用时显示出显著的抑制作用。此外，我们发现，当使用包括整合酶抑制剂在内的抗siv方案治疗时，Ch Rh在血浆中具有最大的抑制（< 30拷贝/ml）病毒，这一壮举尚未在非人灵长类动物模型中实现。我们现在有了一个独特的模型，可以用来验证我们的假设，即肠道是SIV在自发病毒控制者或HAART中最大的储存库，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。我们在此提议：目标1。鉴定经HAART治疗的siv感染猕猴的细胞和组织储藏库以及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，我们将降低治疗NP血浆中的病毒血症至<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存库，以确定主要储存库，我们还将分析使用HAART、不使用HAART和LTNP的NP之间的病毒突变和进化，以检查它们与病毒储存库和联合抗逆转录病毒治疗的关系。目标2。评估在早期SIV感染中，通过将HAART与补充方案或组织靶向策略相结合，从受感染宿主中根除病毒的潜力。新的抗病毒策略不断出现，我们将在siv -猕猴模型中纳入一些最新的抗病毒方案。例如，我们目前正在猕猴中测试融合抑制剂，这些抑制剂可能与上述治疗相结合，试图量化多种药物组合下猕猴细胞和组织储存库的衰变。此外，我们可以利用在Aim1中获得的知识设计针对特定位点的特定策略，以成功根除病毒。这项拟议的研究将为HIV持续存在和潜伏期的机制提供新的见解，并评估根除是否可能是一个可行的目标。最后，这些数据可能为新的治疗方法或疫苗方法确定有用的靶点。