Quantification of HIV Reservoirs in the Gut-Associated Lymphatic System

肠道相关淋巴系统中 HIV 储库的定量

• 批准号: 8312343
• 负责人: Steven A Yukl
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312343
• 关键词: Abdomen; Adverse effects; Affect; Antiviral Agents; Antiviral Therapy; Area; Attenuated; Biological Assay; Biometry; Biopsy; Blood; Blood Cells; CD4 Positive T Lymphocytes; California; Cardiovascular Diseases; Caring; Cell Count; Cell division; Cells; Chronic; Clinical; Clinical Research; Collaborations; DNA; DNA Methylation; Detection; Disease remission; Environment; Epigenetic Process; Faculty; General Hospitals; Genetic Transcription; Grant; HIV; HIV Infections; HIV therapy; HIV-1; Histone Acetylation; Homing; Immune; Immunologics; Immunology; Incidence; Infection; Institutes; Institution; K-Series Research Career Programs; Kidney Diseases; Knowledge; Laboratories; Lead; Life; Liver diseases; Lymphatic System; Malignant Neoplasms; Measures; Medical; Medical center; Medicine; Modification; Molecular; Monitor; Morbidity - disease rate; Nature; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Plasma; Population; Prevalence; Proto-Oncogene Protein c-kit; Proto-Oncogenes; Provider; RNA; Rectum; Research; Research Personnel; Research Training; San Francisco; Site; Staging; Stimulus; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Training; Transcriptional Regulation; Universities; Veterans; Viral; Work; Writing; anergy; antiretroviral therapy; cell type; clinical care; design; experience; ileum; immune activation; improved; latent infection; memory CD4 T lymphocyte; mortality; novel; peripheral blood; prevent; skills; therapy design; transcription factor; viral RNA; virology

DESCRIPTION (provided by applicant): In applying for the VA Career Development Award (CDA), I hope to acquire the experience, skills, and knowledge necessary to become an independent faculty investigator who uses patient-driven research to better understand the obstacles to eradication of HIV. My research background includes: 1) investigating the transcriptional control of the proto-oncogene c-kit; 2) investigating whether the viral transcription factor Tat contributes to latent infection with HIV-1; and 3) investigating HIV levels and immune parameters within different parts of the gut. This CDA will enable me to obtain additional training in several key areas that will facilitate my transition to an independent translational researcher. Specific areas of training include advanced immunology and virology, biostatistics, design and implementation of clinical studies, scientific collaborations, new laboratory techniques, novel assays, and grant writing. The research environment will include the San Francisco VA Medical Center along with the University of California, San Francisco (UCSF) and its affiliated institutions, including San Francisco General Hospital and the Gladstone Institute. These institutions are nationally known for clinical care, training, and research in HIV. This study seeks to improve understanding of how and why HIV persists on antiretroviral therapy by investigating whether the gut is a site of ongoing replication, whether it is a major reservoir of latently-infected CD4+ T cells (or other cellular reservoirs), and how these cells are maintained. The specific aims are: 1) to quantify levels of HIV (DNA, RNA) in different cell populations and subpopulations in both the gut and peripheral blood; 2) to assess for ongoing replication in the ileum by testing for markers that are associated with recent infection; 3) to measure the proportion of each gut cell type with inducible, replication-competent, and/or "latent" HIV; 4) to investigate mechanisms of latency in the gut; and 5) to evaluate the ability of different anti-latency therapies to reactivate HIV from gut cells and tissues. Gut tissue will be obtained primarily via colonoscopic biopsies of the ileum and rectum. In addition, the study will make use of unused tissue from patients who are undergoing abdominal surgery for clinical reasons unrelated to the study. These biopsies and tissues will be used to identify the cell populations with the most HIV DNA and RNA, to measure inducible and/or replication-competent HIV in the gut, to investigate mechanisms of latency in the gut, and to test the effect of different anti-latency therapies. The knowledge thus gained may ultimately contribute to new and improved therapies aimed at eradication or lifelong coexistence with HIV.

描述（由申请人提供）： 在申请VA职业发展奖（CDA）时，我希望获得成为独立的教师调查员所必需的经验，技能和知识，他们使用以患者为导向的研究来更好地了解根除HIV的障碍。我的研究背景包括：1）研究原始癌基因C-KIT的转录控制； 2）研究病毒转录因子是否有助于HIV-1的潜在感染； 3）研究肠道不同部位内的HIV水平和免疫参数。该CDA将使我能够在几个关键领域获得额外的培训，这将促进我向独立翻译研究人员的过渡。培训的特定领域包括先进的免疫学和病毒学，生物统计学，临床研究的设计和实施，科学合作，新的实验室技术，新颖的分析和赠款写作。研究环境将包括旧金山弗吉尼亚州医疗中心，加利福尼亚大学，旧金山大学（UCSF）及其附属机构，包括旧金山综合医院和格拉德斯通研究所。这些机构以HIV的临床护理，培训和研究而闻名。 这项研究旨在通过研究肠道是否是持续复制的部位，是否是潜在受感染的CD4+ T细胞（或其他细胞库）（或其他细胞维持这些细胞）来提高对HIV如何以及为什么持续在抗逆转录病毒疗法上的理解。具体目的是：1）量化不同细胞群体中的HIV水平（DNA，RNA）和肠血和外周血的亚群； 2）通过测试与近期感染相关的标记来评估回肠中持续的复制； 3）用诱导，能力和/或“潜在” HIV测量每种肠道类型的比例； 4）研究肠道潜伏期的机制； 5）评估不同抗延迟疗法从肠道细胞和组织重新激活HIV的能力。肠道组织将主要通过回肠和直肠的结肠镜检查获得。此外，由于与研究无关的临床原因，该研究将利用正在接受腹部手术的患者的未使用的组织。这些活检和组织将用于鉴定具有最多的HIV DNA和RNA的细胞群，以测量肠道中诱导和/或复制能力的HIV，以研究肠道中潜伏期的潜伏期机制，并测试不同抗局部疗法的作用。因此，获得的知识最终可能有助于旨在消除或终身与HIV共存的新疗法和改进的疗法。