Inhibition of HIV-Induced Apoptosis by Host Target Genes

宿主靶基因抑制 HIV 诱导的细胞凋亡

• 批准号: 6590896
• 负责人: TERRI H FINKEL
• 金额: $ 25.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590896
• 关键词: HIV infections; T lymphocyte; apoptosis; cell line; clinical research; free radical oxygen; gene expression; genetic regulation; genetic transduction; helper T lymphocyte; host organism interaction; human immunodeficiency virus; human subject; hypoxia inducible factor 1; molecular cloning; northern blottings; patient oriented research; subtraction hybridization; tissue /cell culture; virus cytopathogenic effect; virus replication

DESCRIPTION (provided by applicant): Ground-breaking research in basic biology has led to an understanding of some of the pathogenic mechanisms of HIV-1 infection. Surprisingly, an unanswered question remains the mechanism(s) by which HIV-1 kills T-cells. We hypothesize that productive infection does not kill all infected cells. Furthermore, we hypothesize that HIV-1 and host cellular targets are both actively involved in regulation of apoptosis during HIV-1 infection. The goal of the proposed investigation is to identify differential gene expression in apoptotic and non-apoptotic HIV-1 infected cells, and to identify and characterize novel or unstudied host cell-specific targets that inhibit apoptosis in infected cells. In preliminary studies, we have identified a set of candidate gene products associated with survival of HIV-1 infected T-cells. The expression level of candidate genes (for example, our novel gene, HALP) will be examined in cells infected with various HIV-1 strains and primary isolates. The role of candidate genes will be evaluated by establishing stable cell lines, or by transducing HIV-infected cells using plasmid or retroviral expression vectors. Transductants expressing HALP or other candidate genes will be evaluated for viability, in the face of productive HIV-1 infection. We hypothesize that constitutive or inducible expression of HALP inhibits apoptosis of HIV-infected T-cells, via the hypoxia-inducible factor-1 (HIF-1) and regulation of reactive oxygen species (ROS). Future goals will include in-depth definition of candidate gene function and development of drugs targeting infected cell viability. It is anticipated that these studies will yield new insights into the pathogenesis of AIDS, identify potential cellular targets that regulate HIV-1 infection, and suggest novel therapeutic approaches for treatment of HIV-infected individuals.

描述（由申请人提供）：基础生物学的突破性研究已经导致对HIV-1感染的一些致病机制的理解。令人惊讶的是，一个悬而未决的问题仍然是HIV-1杀死T细胞的机制。我们假设生产性感染并不能杀死所有被感染的细胞。此外，我们假设HIV-1和宿主细胞靶点都积极参与HIV-1感染期间细胞凋亡的调节。拟议的调查的目标是确定差异基因表达的凋亡和非凋亡的HIV-1感染的细胞，并确定和表征新的或未研究的宿主细胞特异性靶点，抑制感染的细胞凋亡。在初步研究中，我们已经确定了一组与HIV-1感染的T细胞存活相关的候选基因产物。候选基因（例如，我们的新基因HALP）的表达水平将在感染各种HIV-1毒株和原代分离株的细胞中进行检测。候选基因的作用将通过建立稳定的细胞系，或通过使用质粒或逆转录病毒表达载体转导HIV感染的细胞来评估。将评估表达HALP或其他候选基因的转导子在生产性HIV-1感染中的存活力。我们假设HALP的组成性或诱导性表达通过低氧诱导因子-1（HIF-1）和活性氧（ROS）的调节抑制HIV感染的T细胞的凋亡。未来的目标将包括深入定义候选基因的功能和开发针对感染细胞活力的药物。预计这些研究将对艾滋病的发病机制产生新的见解，确定调节HIV-1感染的潜在细胞靶点，并为治疗HIV感染者提出新的治疗方法。