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Host innate immune response as a barrier to cross-species retrovirus transmission

宿主先天免疫反应作为跨物种逆转录病毒传播的屏障

基本信息

批准号：
9886183
负责人：
Amit Sharma
金额：
$ 24.89万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-06 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886183
关键词：
Affect Animal Model Antiviral Agents Biological Biological Models Cell Culture Techniques Cells Chronic Data Development Engineering Gatekeeping Gene Chips Gene Expression Gene Proteins Gene Targeting Genes Genetic Transcription Glycoproteins HIV-1 Human Human immunodeficiency virus test Immunologic Factors In Vitro Infection Innate Immune Response Innate Immune System Integration Host Factors Interferons Life Cycle Stages Lymphocyte Macaca Maps Mentors Methods Modeling Molecular Mutation Pathogenesis Pathogenicity Patients Phase Post-Transcriptional Regulation Prevention Production Property Proteins Research Proposals Resistance Retroviridae Role SIV Therapeutic Therapeutic Studies Time Translations Vaccines Variant Viral Virus Virus Diseases base blocking factor chronic infection clinically relevant cross-species transmission improved in vivo insight mucosal site nonhuman primate novel response transmission process vaccine trial virus host interaction

项目摘要

PROJECT SUMMARY/ABSTRACT The production of type-1 interferons (IFNs) by the host innate immune system presents the first barrier against viral infection. IFNs are innate immune factors that upregulate expression of hundreds of IFN- stimulated genes (ISGs), which results in induction of an “antiviral state”. A small group of ISGs encode proteins that restrict HIV-1 and SIV replication and are referred to as “restriction factors”. Restriction factors are less active against wild-type viruses replicating in their natural host but act as potent barriers against cross- species transmission. Macaque model systems are critical gatekeepers for testing HIV-1 prevention methods and for studies of HIV-1 transmission and pathogenesis. HIV-1 does not persistently infect macaques due to restriction by several macaque-specific restriction factors necessitating the use of chimeric SIV/HIV-1 viruses (SHIVs). Existing SHIV/macaque models typically employ SHIVs that encode HIV-1 sequences from viruses amplified in culture and further adapted in macaques (adapted SHIVs). Development of SHIVs encoding circulating HIV-1 variants derived directly from infected humans (circulating SHIVs) has been challenging as these SHIVs replicate poorly in macaque cells, if at all. While some host restrictions to HIV-1 replication in macaques have been defined, there is limited information on macaque-specific restriction factors that limit replication of circulating HIV-1 variants. Our preliminary results suggest that circulating SHIVs replicate poorly and are potently inhibited by macaque-specific IFN responses despite encoding the SIV antagonists of known restriction factors. In contrast, SHIVs encoding adapted HIV-1 sequences are resistant to IFN inhibition. Thus, this research proposal will characterize the host-viral interactions that selectively restrict replication of circulating SHIVs. During the mentored phase (K99): 1) the viral determinants of macaque-adapted SHIVs that confer resistance to IFN are expected to be defined, and 2) macaque-specific restriction factor(s) against circulating HIV-1 variants is expected to be identified. During the independence phase (R00): 1) characterization of the viral determinants of macaque-adapted SHIVs will be performed. The ability of the adaptive mutations to infect targets cells at the sites of mucosal transmission will be determined, 2) a novel example of cross-species host-viral interaction will be explored by characterizing the post-transcriptional regulation of HIV-1 envelope gene-expression in macaque lymphocytes, and 3) the mechanism of restriction of the macaque-specific restriction factor will be elucidated. Upon completion, this research proposal will successfully integrate the features of clinically relevant circulating HIV-1 variants with species-specific host innate immune system to help understand how macaque- specific IFN responses restrict circulating SHIVs.

项目总结/摘要由宿主先天免疫系统产生的1型干扰素（IFN）是第一道屏障抵抗病毒感染IFN是先天免疫因子，其上调数百种IFN-γ的表达。刺激的基因（ISG），这导致诱导“抗病毒状态”。一小群ISG编码限制HIV-1和SIV复制的蛋白质，称为“限制因子”。限制因素是对在其天然宿主中复制的野生型病毒活性较低，但可作为有效的屏障，物种传播猕猴模型系统是测试HIV-1预防方法和研究 HIV-1的传播和发病机制。HIV-1不会持续感染猕猴，这是由于受到以下限制：几种猕猴特异性限制性因子，需要使用嵌合SIV/HIV-1病毒（SHIV）。现有的SHIV/猕猴模型通常采用SHIV，所述SHIV编码来自在哺乳动物中扩增的病毒的HIV-1序列。培养并在猕猴中进一步适应（适应的SHIV）。编码循环HIV-1的SHIV的开发直接来自受感染的人的变体（循环SHIV）一直具有挑战性，因为这些SHIV 在猕猴细胞中复制很差，如果有的话。虽然猕猴体内HIV-1复制的宿主限制，虽然已经定义，但关于限制复制的猕猴特异性限制因素的信息有限。传播HIV-1变异体。我们的初步结果表明，循环中的SHIV复制较差，并且被尽管编码已知限制因子的SIV拮抗剂，但猕猴特异性IFN应答。与此相反，编码适应的HIV-1序列的SHIV对IFN抑制具有抗性。因此，本研究计划将表征选择性限制循环SHIV复制的宿主-病毒相互作用。在指导阶段（K99）：1）猕猴适应性SHIV的病毒决定因素，对IFN的耐药性，2）猕猴特异性限制因子， HIV-1变异体有望得到鉴定。在独立阶段（R 00）：1）表征的病毒决定因素的猕猴适应将进行SHIV。适应性突变感染粘膜部位靶细胞的能力传播将被确定，2）跨物种宿主-病毒相互作用的一个新的例子将被探索，表征猕猴淋巴细胞中HIV-1包膜基因表达的转录后调节，以及3）阐明猕猴特异性限制因子的限制机制。完成后，这项研究计划将成功地整合临床相关的特点，循环的HIV-1变异体与物种特异性宿主先天免疫系统，以帮助了解猕猴- 特异性IFN应答限制了循环中的SHIV。