Activation of NF-kB by the cytoplasmic domains of HIV and SIV gp41

HIV 和 SIV gp41 胞质结构域对 NF-kB 的激活

• 批准号: 8705773
• 负责人: Michaela Ulrike Gack
• 金额: $ 39.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-09 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705773
• 关键词: Affect; Architecture; Attention; Binding; Biochemical; Biochemical Genetics; CD4 Positive T Lymphocytes; Cell Culture System; Cell physiology; Cells; Complex; Cytoplasmic Tail; Dependence; Enhancers; Event; Exhibits; Foundations; Genes; Genetic Transcription; Glycoproteins; Growth; HIV; HIV Infections; HIV-1; Human; Immune response; In Vitro; Infection; Investigation; Kinetics; Laboratories; Lead; Macaca; Mediating; Mediator of activation protein; Modeling; Molecular; Monkeys; Mutation; NF-kappa B; Natural Immunity; Nuclear; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Property; Proviruses; Role; SIV; SIV envelope protein gp41; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Subfamily lentivirinae; Tissues; Ubiquitination; Viral; Viral Genes; Viral Load result; Virus; Virus Replication; Work; adaptive immunity; base; cell type; comparative; in vivo; insight; mutant; new therapeutic target; nonhuman primate; novel; novel therapeutics; promoter; transcription factor

DESCRIPTION (provided by applicant): HIV, SIV, and related lentiviruses of other species are unusual in that their envelope glycoproteins have very long cytoplasmic domains (CD); however, investigation of the functional contributions of the unusually long CDs has received little attention. The proposed studies will build upon a recent discovery made by the Desrosiers laboratory, that the cytoplasmic domains of gp41 (gp41CD) of both HIV-1 and SIV induce robust activation of the transcription factor NF-?B. Binding studies further revealed that gp41CD of HIV-1, but not SIV, interacts specifically and efficiently with TGF-¿-activated Kinase 1 (TAK1), a key regulator of NF-?B signaling. Replication studies with wild-type HIV-1 and a mutant virus deficient in the ability to activate NF-?B demonstrated that NF-?B activation by gp41CD is important for the virus' ability to replicate in non- or minimally-activated CD4+ T-lymphocytes. These findings demonstrated a novel, evolutionarily conserved role for gp41CD in activating the NF-?B transcription factor. The proposed studies are directed toward investigating in precise detail how the cytoplasmic domains of gp41 (gp41CD) of HIV-1 and SIV lead to activation of NF-?B. Biochemical, genetic, and structural studies will focus on defining the signaling events, cellular interaction partners, and molecular mechanisms of gp41CD-induced NF-?B activation for promoting viral replication (Aim 1). Our studies will further determine the physiologic relevance of gp41CD-induced NF-?B activation for SIV replication and pathogenesis in vivo (Aim 2). Taken together, these studies will not only greatly expand our understanding of the modulation of key signaling pathways by HIV/SIV gp41, but may also define new therapeutic targets for the treatment of HIV infection in humans.

描述（由申请人提供）： HIV，SIV和其他物种的相关慢病毒是不寻常的，因为它们的包膜糖蛋白具有非常长的胞质结构域（CD）;然而，对异常长的CD的功能贡献的研究很少受到关注。拟议的研究将建立在Desrosiers实验室最近的发现，即HIV-1和SIV的gp 41（gp 41 CD）的胞质结构域诱导转录因子NF-？B。结合研究进一步表明，HIV-1的gp 41 CD，而不是SIV，与TGF-β激活的激酶1（TAK 1），NF-κ B的关键调节因子特异性和有效地相互作用。B信令。复制研究与野生型HIV-1和突变病毒缺乏能力，激活NF-？B证明NF-？gp 41 CD激活B对于病毒在非活化或最低活化的CD 4 + T淋巴细胞中复制的能力很重要。这些研究结果表明，一种新的，进化保守的作用gp 41 CD激活NF-？B转录因子。拟议的研究是针对精确的详细调查如何gp 41（gp 41 CD）的HIV-1和SIV的细胞质结构域导致NF-κ B的激活？B。生化，遗传和结构的研究将集中在定义信号事件，细胞相互作用的合作伙伴，和gp 41 CD诱导的NF-？B活化以促进病毒复制（目的1）。我们的研究将进一步确定gp 41 CD诱导的NF-？B激活SIV复制和体内发病机制（目的2）。总之，这些研究不仅将大大扩展我们对HIV/SIV gp 41调节关键信号通路的理解，而且还可能为人类HIV感染的治疗定义新的治疗靶点。