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

• 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
• 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

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.

项目摘要/摘要 宿主先天免疫系统的1型干扰素（IFN）的生产呈现出第一个障碍 反对病毒感染。 IFN是先天免疫因子，上调了数百个IFN-的表达 刺激基因（ISG），导致诱导“抗病毒状态”。一小部分ISG编码 限制HIV-1和SIV复制并被称为“限制因素”的蛋白质。限制因素是 对在其自然宿主中复制的野生型病毒的活跃较小 物种传播。 猕猴模型系统是测试HIV-1预防方法的关键守门人，并研究 HIV-1传播和发病机理。 HIV-1由于受到限制而不会持续感染猕猴 使用嵌合SIV/HIV-1病毒（SHIVS）使用的几种猕猴特异性限制因素。 现有的Shiv/猕猴模型通常采用SHIV，编码来自病毒的HIV-1序列。 培养并进一步适应猕猴（改编后的湿婆）。编码循环HIV-1的SHIV的开发 这些湿暴 如果有的话，在猕猴细胞中复制不佳。猕猴中某些主机对HIV-1复制的限制有 已定义，有关猕猴特异性限制因素的信息有限，该因素限制了复制 循环HIV-1变体。 我们的初步结果表明，循环SHIV复制不佳，并有可能受到 猕猴特异性的IFN响应目的地编码已知限制因子的SIV拮抗剂。相比之下， 编码适应的HIV-1序列的SHIV对IFN抑制具有抗性。那，这项研究建议将 表征有选择地限制循环湿因的复制的宿主病毒相互作用。 在修补阶段（K99）：1）猕猴适应的湿婆的病毒决定剂 预计将定义对IFN的抗性，2）猕猴特异性限制因子针对循环 预计HIV-1变体将被识别。 在独立阶段（R00）：1）猕猴适应的病毒决定剂的表征 将执行SHIV。自适应突变感染靶标细胞在粘膜部位的能力 将确定传输，2）将通过 表征猕猴淋巴细胞中HIV-1包膜基因表达的转录后调节， 3）将阐明猕猴特异性限制因子的限制机理。 完成后，该研究建议将成功整合临床相关的特征 具有特定于规格的宿主先天免疫系统的循环HIV-1变体，以帮助了解猕猴 具体的IFN响应限制了循环湿度。