Persistent HIV-1 Replication in the Respiratory Tract Despite ART

尽管接受了抗逆转录病毒疗法，HIV-1 仍在呼吸道中持续复制

• 批准号: 8307939
• 负责人: Thor Andrew Wagner
• 金额: $ 12.95万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307939
• 关键词: Acute; Address; Adolescent; Adult; Affect; Alveolar Macrophages; Anti-Retroviral Agents; Antigens; Antiretroviral resistance; Blood; Cells; Characteristics; Child; Childhood; Collaborations; Communicable Diseases; Communities; Consultations; DNA; Data; Detection; Drug resistance; Enrollment; Environment; Evolution; Face; Flow Cytometry; Genetic; Genome; Goals; HIV; HIV-1; Immunologic Surveillance; Individual; Infection; Inflammation; Lung; Lymphocyte; Measures; Mentorship; Methods; Microbe; Modeling; Nucleosides; Nucleotides; Participant; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phosphorylation; Phylogenetic Analysis; Plasma; Population; Principal Investigator; Protease Inhibitor; Publishing; RNA; Randomized Clinical Trials; Randomized Controlled Trials; Regimen; Relative (related person); Research; Research Personnel; Respiratory Mucosa; Respiratory System; Respiratory tract structure; Reverse Transcriptase Inhibitors; Risk; Sampling; Site; Sorting - Cell Movement; Source; Specimen; Sputum; Surface; Tenofovir; Time; Treatment Failure; Universities; Viral; Viral Genome; Viral Load result; Virus; Washington; Work; antiretroviral therapy; base; career; cell type; cohort; didactic education; drug resistant virus; efavirenz; insight; macrophage; monocyte; mutant; non-nucleoside reverse transcriptase inhibitors; pediatric human immunodeficiency virus; peripheral blood; programs; receptor; resistance mutation; success; treatment strategy

DESCRIPTION (provided by applicant): Candidate: Dr. Thor Wagner is a senior fellow in Pediatric Infectious Diseases at the University of Washington. His long-term goal is a career in pediatric patient-orientated HIV research. Environment: Dr. Wagner has proposed mentorship from an established pediatric HIV researcher, collaboration and consultation with various local experts, as well as a comprehensive didactic curriculum, that takes advantage of the rich academic HIV research community in Seattle, WA. Research: The hypothesis, HIV-1 replication persists at low levels in macrophages during effective antiretroviral therapy, will be addressed by three aims: (1) evaluate HIV-1 in induced sputa, which is rich in macrophages, for genetic evidence of viral replication over time; (2) determine the relative rate of viral replication in sputa macrophages compared to lymphocytes; (3) explore the relative activity of different antiretroviral regimens, including those with and without drugs that appear to be more active in macrophages, on measures of viral replication in sputum samples. In Aim 1, multiple single-genome HIV-1 sequences (SGS) derived from annual induced sputum specimens and peripheral blood mononuclear cells collected over five years from 15 children will be analyzed for evidence of replication. In Aim 2, sorting of sputa cells by flow cytometry followed by SGS will precisely define the cell types with evidence of viral replication. In Aim 3, HIV-1 replication will be gauged in sputum specimens from adults who are or are not treated with tenofovir and non-nucleoside reverse transcriptase inhibitors, which appear to be more active in macrophages. Relevance: Millions of HIV-1 infected individuals face a lifelong challenge of averting antiretroviral resistance. Persistent low-level viral replication despite antiretroviral therapy substantially increases the risk of antiretroviral resistance. Our studies will provide insight into persistent HIV-1 replication during antiretroviral therapy and whether specific drugs are more effective in suppressing viral replication in macrophages.

描述（由申请人提供）： 候选人：Thor Wagner 博士是华盛顿大学儿科传染病高级研究员。他的长期目标是从事以儿科患者为导向的艾滋病毒研究。环境：瓦格纳博士建议由一位资深儿科艾滋病毒研究人员提供指导，与当地多位专家合作和咨询，以及利用华盛顿州西雅图丰富的艾滋病毒学术研究社区的综合教学课程。研究：在有效的抗逆转录病毒治疗期间，巨噬细胞中 HIV-1 复制持续保持在低水平的假设将通过三个目标来解决：(1) 评估富含巨噬细胞的诱导痰中的 HIV-1，以获取病毒复制的遗传证据随着时间的推移; (2)确定痰巨噬细胞与淋巴细胞中病毒复制的相对速率； (3) 探讨不同抗逆转录病毒治疗方案（包括使用和不使用似乎在巨噬细胞中更活跃的药物的治疗方案）对痰样本中病毒复制的测量的相对活性。在目标 1 中，将对来自 15 名儿童五年内收集的年度诱导痰标本和外周血单核细胞的多个单基因组 HIV-1 序列 (SGS) 进行分析，以获取复制证据。在目标 2 中，通过流式细胞术和 SGS 对痰细胞进行分选，将精确定义具有病毒复制证据的细胞类型。在目标 3 中，将在接受或未接受替诺福韦和非核苷逆转录酶抑制剂治疗的成年人的痰标本中测量 HIV-1 复制，这些抑制剂似乎在巨噬细胞中更活跃。相关性：数百万 HIV-1 感染者面临着避免抗逆转录病毒耐药性的终生挑战。尽管进行了抗逆转录病毒治疗，但持续的低水平病毒复制大大增加了抗逆转录病毒耐药性的风险。我们的研究将深入了解抗逆转录病毒治疗期间 HIV-1 的持续复制，以及特定药物是否能更有效地抑制巨噬细胞中的病毒复制。

项目成果

Quantification of mitochondrial toxicity in HIV-infected individuals by quantitative PCR compared to flow cytometry.

与流式细胞术相比，通过定量 PCR 定量 HIV 感染者的线粒体毒性。

• DOI: 10.1002/cyto.b.21045
• 发表时间: 2013
• 期刊: Cytometry. Part B, Clinical cytometry
• 作者: Wagner,ThorA;Lin,Chen-Han;Tobin,NicoleH;Cote,HeleneCF;Sloan,DerekD;Jerome,KeithR;Frenkel,LisaM
• 通讯作者: Frenkel,LisaM