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

描述（由申请人提供）：这是Devi SenGupta博士的K 08奖申请，Devi SenGupta博士是加州大学旧金山分校弗朗西斯科（UCSF）实验医学部的助理兼职教授，她正在将自己确立为研究人类内源性逆转录病毒（HERV-K（HML-2））在HIV感染中的作用的年轻研究者。HERV是古代感染的残留物，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，它们可能在艾滋病毒感染中被重新激活。HIV感染期间HERV-K再活化的程度和后果尚不完全清楚。SenGupta博士已经证明，HERV特异性CD 8 + T细胞反应与慢性感染中的HIV控制有关，并证明了这些细胞在体外消除HIV和SIV感染细胞的能力。这些数据表明，重新激活的HERV可能作为保守的，宿主编码的艾滋病毒感染的细胞的目标，导致其细胞毒性裂解，他们可以潜在地利用在治疗性疫苗策略。除了控制病毒血症外，SenGupta博士还发现HERV-K表达与未治疗个体的免疫激活水平降低有关。免疫激活是慢性HIV患者发病（包括治疗后CD 4 + T细胞恢复不良）的主要原因。有几个问题需要进一步表征HERV在HIV感染中的复杂作用：HERV-K在感染细胞中的表达如何驱动HERV-K特异性免疫（目的1）？HERV特异性CD 4 + T辅助细胞和调节性（Treg）细胞在HIV中的作用是什么（Aim 2）？最后，HERV-K表达和早期感染中产生的适应性免疫应答如何调节HIV疾病的长期结局，如免疫激活、治疗受试者中的CD 4 + T细胞恢复和未治疗个体中的HIV病毒载量所定义的（目的3）？SenGupta博士将获得专业知识，使她能够作为一名独立的翻译研究者取得成功。为了实现这一目标，SenGupta博士组建了一个由主要导师道格拉斯F.尼克松，医学教授和适应性免疫反应和HERV生物学专家，和两位共同导师：约瑟夫博士“迈克”McCune，在加州大学旧金山分校实验医学部主任，谁进行的研究，在粘膜免疫，和史蒂芬G。Deeks，医学教授在住宅，谁在设计和解释艾滋病毒感染者的良好特征的临床队列研究的具体专业知识。SenGupta博士的研究提案加上结构化的培训计划将使她能够为R 01赠款申请开发必要的技能和初步数据，她将最终研究如何利用HERV-K来创建新的疫苗和根除艾滋病毒的策略。

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.