Role of HIV Tat protein in pathogenesis of HIV dementia

HIV Tat 蛋白在 HIV 痴呆发病机制中的作用

• 批准号: 7460701
• 负责人: AVINDRA NATH
• 金额: $ 35.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460701
• 关键词: AIDS Dementia Complex; Amino Acid Sequence; Amino Acids; Brain; Cell Line; Country; Dementia; Development; Exons; Genes; HIV; HIV tat Protein; Human; Immunosuppression; Infection; Institutes; Integration Host Factors; Mediating; Mutate; Neuroglia; Neurons; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Post-Translational Protein Processing; Production; Property; Proteins; Recombinants; Reporting; Role; Spleen; Therapeutic; Therapeutic immunosuppression; Transcript; Viral Genes; Virus; antiretroviral therapy; brain cell; novel therapeutics; physical property; rev Gene Products; tat Protein

DESCRIPTION (provided by applicant): Current antiretroviral therapy is instituted upon immunosuppression when HIV has already entered the brain. Further, this mode of treatment has no effect on the integrated virus or on the production of early viral gene transcripts such as Tat, Nef and Rev. Of these gene products, only Tat is released extracellularly and has a variety of effects on neurons and glial cells. To date, most studies have been performed by only 1 or 2 Tat proteins derived from HIV clade B, but there is significant divergence in the amino acid sequences between clade B and C derived Tat proteins, even in the so called conserved regions of the gene. Further, HIV clade C virus infects the largest populations in the world, and interestingly little or no dementia has been reported from the clade C infected countries. Although there may be multiple reasons for the differences, very little is known about the functional properties of Tat derived from clade C. Further, the role of the second exon of both clade B and C is poorly understood. Tat also has residues that undergo post-translational modification the functional significance of needs to be characterized. Because of the critical role of Tat in HIV replication and its effects on brain cells, there is need to establish therapeutic approaches that would target this protein or host factors that are critical in mediating Tat effects. We thus propose to 1) determine HIV clade specific differences in Tat effects on brain cells. Tat will be sequenced from brain and spleen from well-characterized patients with HIV clade B and C infections. Recombinant Tat proteins and Tat expressing cell lines will be compared for their functional differences. 2) determine physical properties of Tat necessary for mediating Tat effects on brain cells. The amino acids involved in posttranslational modification will be mutated to determine their role in Tat function. 3) identify novel therapeutic approaches for targeting Tat mediated effects on brain cells. Drugs approved for human use targeted against host proteins that interact with Tat will be screened to determine their therapeutic potential against clade B and C derived Tat proteins.

描述(申请人提供)：目前的抗逆转录病毒治疗是在艾滋病毒已经进入大脑的免疫抑制的基础上开始的。此外，这种治疗方式对整合病毒或早期病毒基因转录本如Tat、Nef和Rev.的产生没有影响。这些基因产物中，只有Tat被细胞外释放，并对神经元和神经胶质细胞有多种影响。到目前为止，大多数研究只对HIV B分支的1或2个TAT蛋白进行了研究，但B分支和C分支的TAT蛋白之间的氨基酸序列存在显著差异，甚至在基因的所谓保守区也是如此。此外，艾滋病毒C类病毒感染了世界上最大的人群，有趣的是，C类感染国家报告的痴呆症很少或根本没有。尽管造成这种差异的原因可能是多方面的，但人们对来自分支C的TAT的功能性质知之甚少。此外，对分支B和C的第二外显子的作用也知之甚少。Tat还含有翻译后修饰的残基，其功能意义有待鉴定。由于TAT在HIV复制中的关键作用及其对脑细胞的影响，需要建立针对这种蛋白质或在介导TAT效应中至关重要的宿主因子的治疗方法。因此，我们建议1)确定HIV分支在TAT对脑细胞影响方面的具体差异。TAT将从具有良好特征的艾滋病毒B和C分支感染患者的大脑和脾中进行测序。将比较重组TAT蛋白和表达TAT的细胞系的功能差异。2)确定介导TAT对脑细胞作用所必需的TAT的物理性质。参与翻译后修饰的氨基酸将发生突变，以确定它们在TAT功能中的作用。3)寻找靶向TAT介导的脑细胞效应的新的治疗方法。针对与TAT相互作用的宿主蛋白的批准用于人类的药物将被筛选，以确定它们针对分支B和C衍生的TAT蛋白的治疗潜力。