Determining the role of human endogenous retroviruses (HERV) in HIV-1 infection

确定人内源性逆转录病毒 (HERV) 在 HIV-1 感染中的作用

• 批准号: 8703002
• 负责人: Devi SenGupta
• 金额: $ 13.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703002
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Antigens; Antiviral Response; Applications Grants; Attention; Automobile Driving; Award; Biological Assay; Biology; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; California; Cell Count; Cells; Chronic; Clinical; Complex; Containment; Coupled; Cross-Sectional Studies; Cytolysis; Cytomegalovirus; Data; Disease Outcome; Elements; Evolution; Flow Cytometry; Fossils; Genome; Goals; Gut associated lymphoid tissue; HERVs; HIV; HIV-1; HIV-2; Host Defense Mechanism; Human; Human Genome; IL2RA gene; Immune response; Immune system; Immunity; Immunologics; In Vitro; Individual; Infection; Lead; Measures; Medicine; Mentors; Mentorship; Messenger RNA; Morbidity - disease rate; Mucosal Immunity; Mutate; Outcome; Patients; Peripheral; Phenotype; Production; Publishing; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Research Proposals; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; San Francisco; Staining method; Stains; Structure; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Tissue Sample; Training; Transcript; Universities; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Virus Replication; Western Blotting; antiretroviral therapy; cohort; cytokine; cytotoxic; design; empowered; env Gene Products; immune activation; improved; innovation; mortality; novel strategies; novel vaccines; peripheral blood; professor; protective effect; protein expression; reconstitution; residence; skills; success; therapeutic vaccine

DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Devi SenGupta, an Assistant Adjunct Professor in the Division of Experimental Medicine at the University of California, San Francisco (UCSF), who is establishing herself as a young investigator studying the role of human endogenous retroviruses (HERV-K(HML-2)) in HIV infection. HERVs are remnants of ancient infections that exist as dormant elements encoded in the human genome. However, they can be reactivated in HIV infection as a result of dysregulated host defense mechanisms. The extent and consequences of HERV-K reactivation during HIV infection are incompletely understood. Dr. SenGupta has shown that HERV-specific CD8+ T cell responses are associated with control of HIV in chronic infection and has demonstrated the ability of these cells to eliminate HIV- and SIV-infected cells in vitro. These data suggest that reactivated HERVs may serve as conserved, host-encoded targets on HIV-infected cells, leading to their cytotoxic lysis, and that they can potentially be exploited in a therapeutic vaccine strategy. In addition to control of viremia, Dr. SenGupta has found that HERV-K expression is associated with decreased levels of immune activation in untreated individuals. Immune activation is a major cause of morbidity (including poor CD4+ T cell recovery on treatment) in chronic HIV. Several questions are necessary for further characterization of the complex role of HERVs in HIV infection: how does HERV-K expression in infected cells drive HERV-K-specific immunity (Aim 1)? What is the role of HERV-specific CD4+ T-helper and regulatory (Treg) cells in HIV (Aim 2)? Finally, how does HERV-K expression and the resulting adaptive immune response in early infection modulate long-term HIV disease outcome as defined by immune activation, CD4+ T cell recovery in treated subjects, and HIV viral load in untreated individuals (Aim 3)? Organized around these aims and guided by both formal coursework and mentorship, Dr. SenGupta will acquire expertise that will enable her to achieve success as an independent translational investigator. To achieve this goal, Dr. SenGupta has assembled a mentoring team comprised of a primary mentor, Dr. Douglas F. Nixon, Professor of Medicine and an expert in adaptive immune responses and HERV biology, and two co-mentors: Dr. Joseph "Mike" McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts research in Tregs and mucosal immunity, and Dr. Steven G. Deeks, Professor of Medicine in Residence, who has specific expertise in designing and interpreting studies of well-characterized clinical cohorts of HIV-infected individuals. Dr. SenGupta's research proposal coupled with a structured training plan will allow her to develop the necessary skills and preliminary data for an R01 grant application in which she will ultimately study how HERV-K can be harnessed to create novel vaccine and eradication strategies against HIV. PROJECT NARRATIVE: HIV/AIDS remains a leading cause of morbidity and mortality in much of the world, calling for a renewed search for innovative vaccine and therapeutic strategies. A novel approach to the problem of how to empower the immune system to target the rapidly mutating human immunodeficiency virus (HIV) utilizes the HIV-driven reactivation of human endogenous retroviruses (HERVs). HERVs are fossils of ancient infections fixed in our genome, and an understanding of how HERVs might affect HIV disease and its associated over-activation of the immune system could lead to potential new therapies for millions of people around the globe.

描述（由申请人提供）：这是为Devi Sengupta博士颁发的K08奖项，他是加利福尼亚大学旧金山分校（UCSF）实验医学部的助理兼职教授，他正在年轻的研究者确立自己的研究员，研究了人类内源性逆转录病毒的作用（Herv-K（Herv-K（Herv-k）（HML-2））（HML-2）。赫尔斯是古代感染的残余物，它们是人类基因组中编码的休眠元素。但是，由于宿主防御机制失调，它们可以在HIV感染中重新激活。 HIV感染期间HERV-K重新激活的程度和后果尚不完全理解。 Sengupta博士表明，HERV特异性CD8+ T细胞反应与慢性感染中的HIV的控制有关，并证明了这些细胞在体外消除HIV和SIV感染的细胞的能力。这些数据表明，重新激活的HERV可以作为HIV感染细胞的保守，宿主编码的靶标，从而导致其细胞毒性裂解，并有可能在治疗性疫苗策略中被利用。除了控制病毒血症外，Sengupta博士还发现，HERV-K的表达与未经治疗个体的免疫激活水平降低有关。免疫激活是慢性HIV中发病率的主要原因（包括治疗中CD4+ T细胞的恢复不良）。进一步表征HERV在HIV感染中的复杂作用是必要的几个问题：感染细胞中的HERV-K表达如何驱动HERV-K特异性免疫力（AIM 1）？ HERV特异性的CD4+ T馆和调节（Treg）细胞在HIV中的作用（AIM 2）是什么？最后，在早期感染中，HERV-K的表达和由此产生的适应性免疫反应如何通过免疫激活，治疗受试者的CD4+ T细胞恢复和未经治疗的个体中的HIV病毒载荷来调节长期的HIV疾病结果（AIM 3）？ Sengupta博士围绕这些目标组织，并在正式的课程工作和指导的指导下，将获得专业知识，使她能够获得独立的翻译调查员的成功。为了实现这一目标，Sengupta博士组建了一支由主要导师组成的指导团队，医学教授，自适应免疫反应和HERV生物学专家Douglas F. Nixon博士，以及两个合同：Joseph“ Mike” Mike'Mccune博士，UCSF，UCSF和MINVEK INVENK ins tregs in treg ins M. Mike of Bergun and M. McCune博士。居住医学教授，他在设计和解释艾滋病毒感染者的临床人群方面具有特定的专业知识。 Sengupta博士的研究建议以及结构化的培训计划将使她能够为R01赠款应用程序开发必要的技能和初步数据，在该应用程序中，她最终将研究如何利用HERV-K来创建针对HIV的新型疫苗和消除策略。 项目叙述：艾滋病毒/艾滋病仍然是世界上大部分发病率和死亡率的主要原因，呼吁重新寻找创新的疫苗和治疗策略。一种新的方法，即如何赋予免疫系统靶向快速突变的人类免疫缺陷病毒（HIV）利用人类内源性逆转录病毒（HERVS）的HIV驱动的重新激活。 HERV是我们基因组中固定的古代感染的化石，对HERV可能如何影响HIV疾病及其相关的免疫系统过度激活的理解可能会导致全球数百万人的潜在新疗法。