Clinical Interventional Studies of HIV Reservoirs

HIV病毒携带者的临床干预研究

• 批准号: 9343940
• 负责人: Frank Maldarelli
• 金额: $ 71.03万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9343940
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; Aftercare; Alkylating Agents; Anti-Retroviral Agents; Antibiotics; Antigens; Anus Neoplasms; Bacteria; Bacterial Translocation; Biopsy; Blood Circulation; Cell Count; Cell division; Cells; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Conduct Clinical Trials; Cross-Over Studies; Cytotoxic Chemotherapy; DNA; DNA Crosslinking Agent; Data; Defect; Distant; Double-Blind Method; Evaluation; Family suidae; Feasibility Studies; Funding; Gastrointestinal tract structure; Genetic Variation; Goals; Gut associated lymphoid tissue; HIV; HIV Drug Resistance Program; HIV Infections; HIV-1; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunization; Immunologics; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Institutional Review Boards; Integration Host Factors; Interferon Alfa-2b; Interferons; Intervention; Laboratories; Lead; Lymphoid Tissue; Malignant Neoplasms; Maps; Medical center; Memory; Military Personnel; Mitomycins; Modeling; Monitor; Natural History; Natural Immunity; Patients; Peripheral Blood Mononuclear Cell; Placebo Control; Plasma; Population Genetics; Positron-Emission Tomography; Process; Production; Protocols documentation; RNA; Radiation; Radiation therapy; Randomized; Reporting; Residual state; Resistance; Retrovirology; Role; Sampling; Seasons; Series; Site; Site Visit; Source; Surface; Techniques; Time; Tissues; Tumor Tissue; United States National Institutes of Health; Universities; Venous blood sampling; Viral; Viremia; Virus; Wood material; antiretroviral therapy; bench to bedside; cell growth; cell type; chemotherapy; crosslink; cytotoxic; design; gastrointestinal; immune activation; in vivo; influenza virus vaccine; influenzavirus; interferon therapy; novel strategies; pandemic influenza; prevent; randomized placebo controlled trial; reactivation from latency; response; rifaximin; seasonal influenza; tool; treatment duration; viral RNA; virus genetics

Fundamental gaps in our understanding of HIV reservoirs preclude a precisely targeted approach to eradication. HIV is neither eliminated nor often controlled by the human immune system, and the immunologic defect(s) responsible for this lack of control are unknown. Two key issues in understanding HIV persistence during therapy are (1) characterizing the relative contributions of active replication and chronic reservoirs to HIV persistence and (2) describing the cell type and activation state of cells chronically infected with HIV, which may identify new approaches to identify, disrupt, and eliminate persistently infected reservoirs. Ultimately, these approaches must be evaluated in vivo in clinical trials. ___Previously, we developed a standard clinical approach to investigating persistence using a strategy of frequent sampling to quantify HIV viremia during an extended baseline evaluation, followed by intensive monitoring of viremia during a targeted intervention, and evaluation of a post-treatment period. This strategy is optimized to quantify the level and variability of viremia prior to intervention, detect the presence of statistically significant changes during intervention, and determine whether any persistent effects or rebound occur after intervention is discontinued. ___In this project, we have developed a number of new studies to explore interventions using the intensification design. These studies will assess the initial efficacy of potential approaches and provide a wealth of patient-derived material to investigate the source and characterize the mechanisms of HIV persistence. ___We have also developed a series of clinical studies to investigate the relative effects of generalized and specific immune activation on persistent HIV viremia and latency reactivation. We hypothesize that HIV reactivation from latently infected cells can occur as a consequence of nonspecific immune activation or activation from anamnestic responses from specific antigenic stimulation. ___To investigate the role of generalized immune activation in HIV persistence, we are investigating processes that lead to nonspecific immune activation in HIV-infected individuals. One prominent mechanism described for such activation is the translocation of bacterial cell products across the gastrointestinal barrier into the systemic circulation; the presence of these bacterial products leads to generalized immune activation and may contribute to activation of immune cells, including HIV-infected cells, leading to persistent viremia. We are investigating the effects of the non-absorbable antibiotic, rifaximin, which reduces bacterial flora within the gastrointestinal tract. In a multisite randomized, double-blind, placebo-controlled crossover study, we are determining whether reductions in bacterial flora in the gut reduces translocation of bacterial cell products, cellular immune activation, and the level of persistent viremia in patients with viral RNA levels suppressed below 50 copies/ml plasma on combination antiretroviral therapy. The protocol "A Double Blind Randomized Placebo Controlled Study Examining the Effects of a Non-absorbable (Rifaximin) Antibiotic on the Chronic Immune Activation Observed in HIV-infected Subjects" (13-I-0062) is open at NIH and at two additional sites, Walter Reed National Military Medical Center (A. Ganesan) and University of Pittsburgh (D. McMahon). The NIH is the coordinating center for this study. These studies will directly address the role of chronic immune activation in persistent viremia. ___In the past year we successfully applied for new Bench to Bedside funds to investigate the sources of HIV persistence. In the new study "Localizing Reservoirs of HIV Persistence in Lymphoid Tissue," we will be collaborating with B. Wood, A. Venkatesan, and D. Hammoud from InterventionalRadiology to localize and biopsy metabolically active tissue obtained using PET scanning and a specific targeting biopsy technique pioneered by Drs. Wood and Venkatesan. ___A second possible source of immune activation to drive HIV production is potent antigenic stimulation resulting in activation of memory cells containing latent HIV, resulting in increases in virus production. At any given time, a subset of latently infected cells may be responding to cognate antigens and undergoing activation, resulting in virus expression contributing to persistent HIV viremia. We are investigating whether administration of a common recall antigen results in increases in persistent viremia. Our hypothesis is that interventions that expose the immune system to recall antigens will result in increases in plasma HIV RNA levels. We investigated the feasibility of studying specific antigenic stimulation and HIV viremia by determining the effects of the administration of seasonal and pandemic influenza vaccine on levels of persistent viremia. The 2009-2010 influenza season was characterized by circulation of H3N2, H1N1 (seasonal), B, and H1N1 (swine/pandemic) influenza viruses. We performed a pilot substudy of the natural history study of HIV infection 95-I-0072, and obtained additional phlebotomy from patients with suppressed viremia undergoing ART who were receiving influenza vaccination. ___We are also determining the relative effects of cellular expansion on the levels of persistent HIV viremia and latency reactivation. The presence of persistent plasma clones during persistent viremia during therapy suggests that viremia may in part derive from cells undergoing cell division, expanding the reservoir of infected cells without affecting viral genetic diversity. These and other data suggest that cells with proliferative capacity are potential sources of HIV reservoirs. We are collaborating with R. Yarchoan (NCI HIV and AIDS Malignancy Branch) in a study of administration of cytotoxic chemotherapy and local radiation therapy for HIV-associated anal neoplasms (11-C-0129). Adapting the intensification model, patients with suppressed viremia are undergoing additional phlebotomy to obtain plasma and PBMC before, during, and after cycles of chemotherapy with the alkylating agent 5-fluorocuracil and DNA crosslinking agent mitomycin C (N=15). In addition, patients will be sampled during and following subsequent periods of radiation. Our hypothesis is that, by suppressing cell division, alkylating and crosslinking agents will result in decreases in HIV viremia, especially in patients with PPC, but local radiation will not result in changes in HIV RNA. In addition, we will analyze HIV population genetics from plasma, PBMC, and from GALT obtained from regions proximal and distant to the tumor tissue to determine whether changes in viremia can be mapped to specific reservoirs. Protocol 11-C-0129 is open at NIH and is currently accruing patients. ___Innate immune responses have critical effects on the course of HIV infection, and we are also determining the effects of innate immune modulator interferon alpha 2b on levels of persistent HIV viremia and latency reactivation. Our hypothesis is that HIV plasma viremia will be reduced early during interferon therapy, with consequent increases in cell-associated HIV RNA but not HIV DNA, due to tetherin-induced effects preventing HIV release from cells. With time on interferon, we anticipate a decline in infected cell number as infected cells with increased surface HIV will be more easily identified by immune cells. This trial (11-I-0057, "Effect of Interferon Alpha 2b Intensification on HIV-1 Residual Viremia in Individuals Suppressed on Antiretroviral Therapy") is a collaborative study with Dr. McMahon (University of Pittsburgh) and is IRB approved and ongoing. ___[Corresponds to Project 2 in the October 2011 site visit report of the Clinical Retrovirology Section, HIV DRP]

我们对艾滋病毒水库的理解的基本差距排除了精确的根除方法。艾滋病毒既不被人类免疫系统消除，也没有经常控制，也未知造成这种缺乏控制的免疫缺陷。在治疗过程中了解HIV持久性的两个关键问题是（1）表征主动复制和慢性储层对HIV持久性的相对贡献，以及（2）描述慢性感染HIV的细胞类型和激活状态，这些细胞可能会鉴定出鉴定，破坏，消除持久感染的储层。最终，必须在临床试验中对这些方法进行体内评估。 ___Previously, we developed a standard clinical approach to investigating persistence using a strategy of frequent sampling to quantify HIV viremia during an extended baseline evaluation, followed by intensive monitoring of viremia during a targeted intervention, and evaluation of a post-treatment period.优化了该策略，以量化干预前病毒血症的水平和变异性，检测干预过程中统计学上显着变化的存在，并确定在干预后是否发生任何持续的影响或反弹。 ___在这个项目中，我们开发了许多新的研究，以使用强化设计探索干预措施。这些研究将评估潜在方法的初始功效，并提供大量患者衍生的材料来研究来源并表征HIV持久性的机制。 ___我们还开发了一系列临床研究，以研究广义和特异性免疫激活对持续性HIV病毒血症和潜伏期重新激活的相对影响。我们假设，由于非特异性的免疫激活或因特定抗原刺激而引起的厌食反应激活而导致的潜在感染细胞的HIV重新激活可能发生。 ___研究普遍化的免疫激活在HIV持久性中的作用，我们正在研究导致HIV感染个体非特异性免疫激活的过程。描述的这种激活的一种突出的机制是细菌细胞产物穿过胃肠道屏障进入全身循环的易位。这些细菌产物的存在会导致普遍的免疫激活，并可能有助于免疫细胞的激活，包括感染HIV的细胞，导致持续性病毒血症。我们正在研究不可吸收的抗生素Rifaximin的作用，从而降低了胃肠道内的细菌菌群。在一项多站点随机的，双盲的，安慰剂对照的跨界研究中，我们确定肠道中细菌菌群的降低是否减少了细菌细胞产物的易位，细胞免疫激活以及病毒RNA水平抑制50份副本/mL等离子体的持续性病毒血症的持续性病毒血症水平。该方案“一项双盲随机安慰剂对照研究，研究了不可吸收（利法西蛋白）抗生素对在HIV感染受试者中观察到的慢性免疫激活的影响”（13-i-i-0062）在NIH开放，在两个其他地点在沃尔特·里德国家军事医学中心（A. Ganesan）和Pittsburgh（A. Ganesan）和Pittsburgh（A. Ganesan）和D.Mcmah（沃尔特·瑞德（Walter））开放。 NIH是本研究的协调中心。这些研究将直接解决慢性免疫激活在持久性病毒血症中的作用。 ___在过去的一年中，我们成功地申请了新的长凳来床头资金，以调查艾滋病毒持久性的来源。在新的研究“淋巴组织中HIV持久性的定位库”中，我们将与B. Wood，A。Venkatesan和D. hammoud合作，从干预瓦拉放射学到使用PET扫描获得的定位和活检的本地化和活检，并使用PET扫描和特定的靶向靶向活检技术通过DRS进行了pioneepersy。木材和Venkatesan。 ____二次可能的免疫激活来源驱动HIV产生的是有效的抗原刺激，导致含有潜在艾滋病毒的记忆细胞激活，从而导致病毒产生的增加。在任何给定的时间，一部分受感染的细胞可能会对同源抗原作出反应和激活，从而导致病毒表达导致持续性HIV病毒血症。我们正在调查常见抗原的给药是否会导致持续性病毒血症的增加。我们的假设是，暴露于免疫系统回忆抗原的干预措施将导致血浆HIV RNA水平升高。我们通过确定季节性和大流行性流感疫苗对持续性病毒血症水平的施用来研究特定抗原刺激和HIV病毒血症的可行性。 2009-2010流感季节的特征是H3N2，H1N1（季节性），B和H1N1（猪/大流行）流感病毒的循环。我们对HIV感染95-I-0072的自然史研究进行了试点，并从接受流感疫苗接种的ART的抑制病毒血症患者那里获得了额外的静脉切开术。 ___我们还确定细胞扩张对持续性HIV病毒血症和潜伏期重新激活水平的相对影响。治疗期间持续性病毒血症期间持续的血浆克隆的存在表明，病毒血症可能部分来自经历细胞分裂的细胞，从而扩大了受感染细胞的储层而不会影响病毒遗传多样性。这些和其他数据表明，具有增殖能力的细胞是HIV储层的潜在来源。我们正在与R. Yarchoan（NCI HIV和AIDS恶性分支）合作，以研究细胞毒性化学疗法和局部放射治疗，用于HIV相关的肛门肿瘤（11-C-0129）。调整强化模型，抑制病毒血症的患者正在接受额外的静脉切开术，以在用烷基化剂5-氟西拉纤维和DNA交叉链接剂Mitymycin C（n = 15）的化学疗法周期之前，期间和之后获得血浆和PBMC（n = 15）。此外，将在随后的放射线期间和之后对患者进行采样。我们的假设是，通过抑制细胞分裂，烷基化和交联剂将导致HIV病毒血症的降低，尤其是在PPC患者中，但局部辐射不会导致HIV RNA的变化。此外，我们将分析来自血浆，PBMC的HIV种群遗传学，以及从近端和远距离肿瘤组织区域获得的GALT，以确定是否可以将病毒血症的变化映射到特定的储层中。协议11-C-0129在NIH开放，目前正在累积患者。 _____INNATE免疫反应对HIV感染的过程有关键影响，我们还确定了先天免疫调节剂干扰素α2B对持续性HIV病毒血症和潜伏期重新激活水平的影响。我们的假设是，在干扰素治疗期间，HIV血浆病毒血症的早期将降低，从而增加了与细胞相关的HIV RNA，而不是HIV DNA的增加，这是由于Tetherin诱导的效应，从而阻止了HIV从细胞中释放出HIV。随着干扰素的时间，我们预计被感染的细胞数量会下降，因为感染了表面HIV增加的细胞将更容易被免疫细胞鉴定出来。该试验（11-I-0057，“干扰素α2B强化对抑制抗逆转录病毒疗法的个体中HIV-1残留病毒血症的影响”是与麦克马洪博士（匹兹堡大学）的一项合作研究，并且已批准IRB批准和正在进行。 ___ [对应于2011年10月的项目2临床逆转录病毒科的现场访问报告，艾滋病毒DRP]