Host Innate Immune Response as a Barrier to Cross-Species Retrovirus Transmission

宿主先天免疫反应是逆转录病毒跨物种传播的屏障

基本信息

批准号：
9312219
负责人：
Amit Sharma
金额：
$ 9.7万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-06 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312219
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 clinically relevant 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.

项目概要/摘要宿主先天免疫系统产生 1 型干扰素 (IFN) 是第一道屏障干扰素是抵抗病毒感染的先天免疫因子，可上调数百种干扰素的表达。刺激基因（ISG），导致诱导“抗病毒状态”。限制 HIV-1 和 SIV 复制的蛋白质被称为“限制因子”。对在自然宿主中复制的野生型病毒活性较低，但可作为防止交叉病毒的有效屏障物种传播。猕猴模型系统是测试 HIV-1 预防方法和研究的关键守门人 HIV-1 的传播和发病机制由于受到限制而不会持续感染猕猴。一些猕猴特异性限制因素需要使用嵌合 SIV/HIV-1 病毒 (SHIV)。现有的 SHIV/猕猴模型通常使用编码 HIV-1 序列的 SHIV，这些序列来自在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。直接源自受感染人类（循环性 SHIV）的变种一直具有挑战性，因为这些 SHIV 虽然 HIV-1 在猕猴体内的复制存在一些宿主限制，但它们在猕猴细胞中的复制效果却很差。已被定义，关于限制复制的猕猴特异性限制因素的信息有限流行的 HIV-1 变种。我们的初步结果表明，循环中的 SHIV 复制能力较差，并受到以下物质的有效抑制：尽管编码了已知限制因子的 SIV 拮抗剂，但猕猴特异性的 IFN 反应却相反。编码适应的 HIV-1 序列的 SHIV 对 IFN 抑制具有抵抗力。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) 适应猕猴的 SHIV 的病毒决定因素预计将确定对干扰素的耐药性，以及 2) 猕猴针对循环系统的特异性限制因素 HIV-1 变异体预计将被识别。在独立阶段（R00）：1）适应猕猴的病毒决定因素的表征将进行 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）将探索跨物种宿主-病毒相互作用的新例子表征猕猴淋巴细胞中 HIV-1 包膜基因表达的转录后调控， 3)阐明猕猴特异性限制因子的限制机制。完成后，该研究计划将成功整合临床相关的特征具有物种特异性宿主先天免疫系统的循环HIV-1变异体有助于了解猕猴如何特定的干扰素反应限制了 SHIV 的循环。