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

项目摘要/摘要 宿主先天性免疫系统产生的1型干扰素(IFN)是第一个障碍 对抗病毒感染。干扰素是一种先天免疫因子，可上调数百种干扰素的表达。 刺激基因(ISGs)，导致诱导一种“抗病毒状态”。一小群ISG编码 限制HIV-1和SIV复制的蛋白质被称为“限制因子”。制约因素有 对在其自然宿主中复制的野生型病毒的活性较低，但对交叉病毒具有强大的屏障作用 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。由于受到限制，HIV-1不会持续感染猕猴 几个猕猴特有的限制因素需要使用SIV/HIV-1嵌合病毒(SHIV)。 现有的SHIV/猕猴模型通常使用SHIV，它编码来自于 培养，并进一步适应猕猴(适应的SHIV)。编码HIV-1循环毒株的研究进展 直接来自受感染人类的变种(循环中的SHIV)一直具有挑战性，因为这些SHIV 在猕猴细胞中复制很差，如果真的有复制的话。虽然一些宿主对猕猴体内HIV-1复制的限制 ，关于限制复制的猕猴特异性限制因素的信息有限 正在传播的HIV-1变种。 我们的初步结果表明，循环中的SHIV复制很差，并被有效地抑制 猕猴特异性的干扰素反应，尽管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对干扰素抑制具有抵抗力。因此，这项研究提案将 描述选择性地限制循环SHIV复制的宿主-病毒相互作用。 在指导阶段(K99)：1)猕猴适应SHIV的病毒决定因素 对干扰素的抵抗力有望被确定，以及2)猕猴特异性限制因子(S)抗循环 预计将确定HIV-1变种。 在独立期(R00)：1)猕猴适应病毒决定因素的特征 将会执行切割法。适应性突变感染粘膜部位靶细胞的能力 将确定传播，2)将通过以下方式探索跨物种宿主-病毒相互作用的新例子 猕猴淋巴细胞中HIV-1外膜基因表达的转录后调控特征， 3)阐明猕猴特异性限制因子的作用机制。 完成后，这项研究提案将成功地整合临床相关的特征 利用物种特异性宿主固有免疫系统循环使用HIV-1变异株，以帮助了解猕猴是如何- 特异性干扰素反应限制循环中的SHIV。

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.