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: 8466830
• 负责人: Devi SenGupta
• 金额: $ 13.1万
• 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/8466830
• 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 Devi SenGupta 博士的 K08 奖申请，Devi SenGupta 博士是加州大学旧金山分校 (UCSF) 实验医学部的助理教授，她正在成为一名年轻的研究者，研究人类内源性逆转录病毒 (HERV-K(HML-2)) 在 HIV 感染中的作用。 HERV 是古代感染的残余物，作为人类基因组中编码的休眠元件存在。然而，由于宿主防御机制失调，它们可能在 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清楚。 SenGupta 博士表明，HERV 特异性 CD8+ T 细胞反应与慢性感染中 HIV 的控制相关，并证明这些细胞能够在体外消除 HIV 和 SIV 感染细胞。这些数据表明，重新激活的 HERV 可能作为 HIV 感染细胞上保守的宿主编码靶标，导致其细胞毒性裂解，并且它们有可能被用于治疗性疫苗策略。除了控制病毒血症之外，SenGupta 博士还发现，HERV-K 表达与未经治疗的个体免疫激活水平降低有关。免疫激活是慢性 HIV 发病的主要原因（包括治疗后 CD4+ T 细胞恢复不良）。为了进一步表征 HERV 在 HIV 感染中的复杂作用，有必要解决几个问题：受感染细胞中的 HERV-K 表达如何驱动 HERV-K 特异性免疫（目标 1）？ HERV 特异性 CD4+ T 辅助细胞和调节性 (Treg) 细胞在 HIV 中发挥什么作用（目标 2）？最后，早期感染中的 HERV-K 表达和由此产生的适应性免疫反应如何调节长期 HIV 疾病结果，定义为免疫激活、治疗受试者中的 CD4+ T 细胞恢复以及未治疗个体中的 HIV 病毒载量（目标 3）？围绕这些目标进行组织，并在正式课程和指导的指导下，森古普塔博士将获得专业知识，使她能够作为一名独立的转化研究者取得成功。为了实现这一目标，SenGupta 博士组建了一个指导团队，其中包括一位主要导师、医学教授、适应性免疫反应和 HERV 生物学专家 Douglas F. Nixon 博士，以及两位联合导师：加州大学旧金山分校实验医学部主任、从事 Tregs 和粘膜免疫研究的 Joseph "Mike" McCune 博士和 Steven G. Deeks 博士。 住院医学教授，在设计和解释具有良好特征的艾滋病毒感染者临床队列研究方面拥有特定的专业知识。 SenGupta 博士的研究计划加上结构化的培训计划将使她能够为 R01 拨款申请开发必要的技能和初步数据，最终她将研究如何利用 HERV-K 来创建针对 HIV 的新型疫苗和根除策略。 项目叙述：艾滋病毒/艾滋病仍然是世界许多地区发病和死亡的主要原因，需要重新寻找创新的疫苗和治疗策略。针对如何增强免疫系统针对快速突变的人类免疫缺陷病毒 (HIV) 的问题，一种新方法利用了 HIV 驱动的人类内源性逆转录病毒 (HERV) 的重新激活。 HERV 是固定在我们基因组中的古代感染的化石，了解 HERV 如何影响 HIV 疾病及其相关的免疫系统过度激活可能会为全球数百万人带来潜在的新疗法。