Clinical Interventional Studies of HIV Reservoirs

HIV病毒携带者的临床干预研究

基本信息

批准号：
10926218
负责人：
Frank Maldarelli
金额：
$ 71.3万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926218
关键词：
Adverse effects Affect Anatomy Angiolymphoid hyperplasia Anti-Inflammatory Agents Antibiotics Antigens Antineoplastic Agents Award Bacterial Translocation Binding Biopsy Blood CCR CD4 Positive T Lymphocytes Cells Clinical Clinical Protocols Clinical Research Clonal Expansion Collaborations Cryptococcal Meningitis Data Defect Disease Event Goals HIV HIV Infections HIV therapy HIV vaccine HIV/AIDS Human Immune response Immune system Immunologics Immunomodulators Individual Infection Inflammatory Integration Host Factors Interferon Alfa-2b Interferons Interruption Intervention Intervention Studies Interventional radiology Kaposi Sarcoma Location Long-Term Effects Lymphoid Tissue Lymphoma Malignant Neoplasms Metabolic Modality National Institute of Allergy and Infectious Disease Natural Immunity Patients Peripheral Blood Lymphocyte Phylogenetic Analysis Plasma Population Positron-Emission Tomography Primates Production Progressive Multifocal Leukoencephalopathy Protocols documentation Regimen Research Personnel Resistance Retrovirology Role SARS-CoV-2 infection Sampling Series Site Source Squamous cell carcinoma Structure Syndrome Therapeutic Tuberculosis United States National Institutes of Health Vaccination Vaccines Viral Viremia antiretroviral therapy candidate identification chemotherapy chimeric antigen receptor T cells clinical center clinical effect co-infection comorbidity cytotoxic design driving force experience fluorodeoxyglucose gastrointestinal gut microbiome immune activation immune reconstitution in vivo interferon therapy microbiome multidisciplinary neoplastic response rifaximin therapeutic vaccine vaccine trial

项目摘要

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. We are conducting several studies to investigate the effects of clinical events on HIV reservoirs. We have established useful collaborations to investigate the effects of clinical interventions on HIV reservoirs. We are collaborating with R. Yarchoan (HIV and AIDS Malignancy Branch, NCI) to study individuals with HIV infection and comorbid cancer treated at the NIH Clinical Center. These study patients receive antineoplastic cytotoxic and immune modulator therapy to treat cancers, treatment modalities that may also have significant effects on HIV-infected cells, and we are studying the effects of these therapies on HIV reservoirs. In collaboration with I. Sereti (NIAID), we are studying patients with advanced HIV/AIDS who initiate antiretroviral therapy (ART) and experience immune reconstitution inflammatory syndrome (IRIS) in response to coinfections such as tuberculosis cryptococcal meningitis, and progressive multifocal leukoencephalopathy (PML). IRIS results in a vigorous immune response to the comorbid infection with significant increases in CD4 T cells; as such, IRIS may have profound effects on HIV reservoirs. We have been studying individuals with IRIS and TB and found that HIV-infected cells are part of the robust immune response that occurs during IRIS. In fact, HIV-infected cells can specifically respond to TB antigens. We have also found that IRIS has long-term effects on the structure of HIV populations during therapy, suggesting IRIS may alter HIV reservoirs. In collaborations with Irini Sereti (NIAID) we have recently demonstrated the effects of PML-IRIS on HIV populations. In addition, we demonstrated that treating IRIS with anti-inflammatory agents can reduce the production of HIV from reservoirs over 100-fold. These studies point to new studies to manipulate the composition and production of HIV populations during therapy. Understanding additional forces that can affect HIV reservoirs have also been initiated. Antineoplastic chemotherapy may have profound effects on HIV populations and we are working with CCR investigators (Drs. K. Lurain, R. Ramaswami, R. Yarchoan) to investigate the effects of new chemotherapeutic regimens for Kaposi Sarcoma, Primary effucsion lymphoma, and Castlemans disease on HIV populations. In addition, we are now investigating the effects of the SARS-CoV-2 infection and vaccination. We have also initiated a new analytic treatment interruption study to determine the sources of rebound viremia when HIV therapy is interrupted (NIH protocol 000277). For these studies, we are conducting a multidisciplinary analysis of HIV reactivation. We use state of the art 18FDG positron emission tomography to characterize metabolic activity of lymphoid tissue, followed by site directed biopsy approach pioneered by our collaborators in NIH interventional radiology. We are quantifying the size and composition of HIV populations in biopsies and blood derived samples prior to and following a short (10 day) treatment interruption,and analyze these data in the context of detailed immunologic studies. As a result, we will obtain a comprehensive analysis of the earliest steps in HIV reactivation. We are also completing a clinical study (NIH protocol 13-I-0062) investigating generalized immune activation in the gastrointestinal-associated lymphoid tissue (GALT) on persistent HIV in individuals undergoing ART. We have been studying the effects of the nonabsorbable antibiotic rifaximin to specifically alter the gut microbiome and affect translocation of bacterial cell products, and the consequent levels of generalized immune activation and low-level HIV viremia. Although we identified changes in the gut microbiome, these changes did not result in downstream effects on levels of HIV viremia or levels of immune activation. These studies will further our understanding of the role of modifying the microbiome in immune activation. We are also investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b. We have characterized the effects of exogenous interferon therapy in a series of HIV-infected individuals undergoing ART (NIH protocol 11-I-0057). We found no effect of interferon on levels of HIV in plasma or in peripheral blood lymphocytes, and are now characterizing interferon effects on the phylogenetic structure of the HIV populations. Our studies of HIV reservoirs indicate a critical role of anatomic locations, particularly lymphoid tissues, in HIV persistence. In a new studies, we are collaborating with Dr. S. Norberg in his CAR-T studies, which now have been expanded to include therapy for squamous cell carcinoma in HIV infected individuals. Dr. Norborg studies have been awarded additional support through CCR Flex award. Finally, we have initiated new collaboration with Dr. Genoveffa Franchini from NCI Vaccine Branch to evaluate new HIV vaccines based on highly successful candidates identified in primate studies. These studies are also expected to generate new studies of the effects of such agents in therapeutic vaccine studies as well.

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。我们正在进行几项研究，以研究临床事件对HIV储层的影响。我们已经建立了有用的合作，以研究临床干预措施对HIV水库的影响。我们正在与R. Yarchoan（HIV和AIDS恶性分支，NCI）合作研究在NIH临床中心接受HIV感染和合并症的患者。这些研究患者接受抗肿瘤的细胞毒性和免疫调节剂治疗以治疗癌症，治疗方式可能对HIV感染的细胞产生重大影响，我们正在研究这些疗法对HIV储层的影响。我们正在与I. Sereti（NIAID）合作，我们正在研究启动抗逆转录病毒疗法（ART）的晚期艾滋病毒/艾滋病患者，并经历了免疫重建炎症综合征（IRIS），以应对结核病脑膜炎等共同感染，以应对共同感染。虹膜导致对合并症感染的剧烈免疫反应，CD4 T细胞显着增加。因此，虹膜可能会对艾滋病毒储量产生深远的影响。我们一直在研究患有虹膜和结核病的个体，发现感染HIV的细胞是虹膜期间发生的可靠免疫反应的一部分。实际上，感染HIV的细胞可以对结核病抗原有特殊反应。我们还发现，IRIS在治疗过程中对HIV群体的结构有长期影响，这表明IRIS可能会改变HIV储层。在与Irini Sereti（NIAID）的合作中，我们最近证明了PML-IRI对HIV种群的影响。此外，我们证明了用抗炎药处理虹膜可以减少100倍以上的储层中的HIV产生。这些研究表明，在治疗过程中操纵HIV群体的组成和产生的新研究。还已经开始了解可能影响艾滋病毒水库的其他力量。抗塑性化学疗法可能对HIV群体产生深远的影响，我们正在与CCR研究者（K. Lurain博士，R。Ramaswami，R。Ramaswami，R。Yarchoan）一起研究Kaposi Sarcoma对Kaposi Sarcoma的影响，对Kaposi Sarcoma的影响，原发性效率淋巴瘤和Castleans疾病对HIV人群。此外，我们现在正在研究SARS-COV-2感染和疫苗接种的影响。我们还开始了一项新的分析治疗中断研究，以确定HIV治疗中断时的反弹病毒血症来源（NIH方案000277）。对于这些研究，我们正在进行对HIV重新激活的多学科分析。我们使用ART 18FDG正电子发射断层扫描的状态来表征淋巴组织的代谢活性，然后由我们的合作者在NIH介入放射学领域进行了定向活检方法。我们正在量化在短暂（10天）治疗中断之前和之后的活检中和血液中艾滋病毒群体的大小和组成，并在详细的免疫学研究的背景下分析这些数据。结果，我们将对HIV重新激活的最早步骤进行全面分析。我们还完成了一项临床研究（NIH方案13-I-0062），该研究研究了胃肠道相关的淋巴组织（GALT）在接受ART的个体中的持续性HIV中的广义免疫激活。我们一直在研究不可吸收的抗生素利福昔明特异性改变肠道微生物组并影响细菌细胞产物的易位的作用，以及随之而来的普遍免疫激活和低水平HIV病毒血症的水平。尽管我们确定了肠道微生物组的变化，但这些变化并未导致对HIV病毒血症水平或免疫激活水平的下游影响。这些研究将进一步理解修饰微生物组在免疫激活中的作用。我们还通过研究先天免疫调节剂干扰素α2B的影响来研究先天免疫在HIV持久性中的作用。我们表征了外源干扰素治疗在一系列接受ART的HIV感染者中的影响（NIH方案11-I-0057）。我们发现干扰素对血浆或外周血淋巴细胞中HIV水平没有影响，现在正在表征干扰素对HIV群体的系统发育结构的影响。我们对HIV储层的研究表明，解剖位置，尤其是淋巴组织在HIV持久性中的关键作用。在一项新研究中，我们正在与S. Norberg博士合作进行他的CAR-T研究，该研究已扩大，包括在HIV感染的个体中为鳞状细胞癌的治疗。 Norborg博士研究通过CCR Flex奖获得了额外的支持。最后，我们与NCI疫苗分支机构的Genoveffa Franchini博士开始了新的合作，以根据灵长类动物研究中确定的非常成功的候选人来评估新的HIV疫苗。这些研究还预计还将对此类药物在治疗性疫苗研究中的影响产生新的研究。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New Approaches to Multi-Parametric HIV-1 Genetics Using Multiple Displacement Amplification: Determining the What, How, and Where of the HIV-1 Reservoir.

DOI：
10.3390/v13122475
发表时间：
2021-12-10
期刊：
Viruses
影响因子：
0
作者：
Patro SC;Niyongabo A;Maldarelli F;Kearney MF
通讯作者：
Kearney MF

Sequential CCR5-Tropic HIV-1 Reactivation from Distinct Cellular Reservoirs following Perturbation of Elite Control.

DOI：
10.1371/journal.pone.0158854
发表时间：
2016
期刊：
PloS one
影响因子：
3.7
作者：
Watters SA;Mlcochova P;Maldarelli F;Goonetilleke N;Pillay D;Gupta RK
通讯作者：
Gupta RK

Eight-day Inpatient Directly Observed Therapy for Antiretroviral Therapy (ART) Failure: A Tool For Preventing Unnecessary ART Changes and Optimizing Adherence Support.

针对抗逆转录病毒治疗 (ART) 失败的八天住院患者直接观察治疗：预防不必要的 ART 改变和优化依从性支持的工具。

DOI：
10.1093/cid/ciz590
发表时间：
2020
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Winchester,NicoleE;Maldarelli,Frank;Mejia,Yolanda;Dee,Nicola;Dewar,Robin;Laidlaw,Elizabeth;Kuriakose,SafiaS;Stoll,Pamela;Proschan,Michael;Lane,HClifford;Pau,AliceK
通讯作者：
Pau,AliceK

Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection.