Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom.
Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom
J Virol. 2019 May 15;93(11). doi: 10.1128/JVI.02123-18. Print 2019 Jun 1.
Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence. Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.
人类免疫缺陷病毒 1 型（HIV-1）感染与异常免疫激活有关；然而，HIV-1 的大多数模型系统都在已建立的感染期间使用。在这里，我们利用超灵敏 HIV-1 定量来描绘人类化小鼠 HIV-1 感染的潜伏期、爆发期和慢性期的早期事件。我们表明，在感染的早期，HIV-1 抑制外周 I 型干扰素（IFN）和干扰素刺激基因（ISG）反应，包括 HIV-1 限制因子 IFI44。在先天免疫激活的高峰期，即在 CD4 T 细胞丢失之前，HIV-1 感染以不同的方式影响 T 细胞和巨噬细胞中外周和淋巴 Toll 样受体（TLR）的表达谱。这导致核因子 κB（NF-κB）、TANK 结合激酶 1（TBK1）和干扰素调节因子 3（IRF3）的激活趋势发生改变。随后的 I 型和 III 型 IFN 反应导致外周 ISG 反应的优先诱导。在最初的先天免疫激活之后，HIV-1 限制因子 SAM 结构域和 HD 结构域包含蛋白 1（SAMHD1）的外周表达恢复到未感染小鼠观察到的水平以下，这表明 HIV-1 干扰了它们的基础表达。然而，外周细胞仍然保留对外源 I 型 IFN 的反应性，而脾细胞对 IFN 的反应显示出一些 ISG 的减少。这证明了非常早期 HIV-1 感染的高度动态性质，并表明诱导 HIV-1 限制因子的阻断有助于病毒持续存在的建立。人类免疫缺陷病毒 1 型（HIV-1）感染仅限于人类和一些非人类灵长类动物（例如，黑猩猩和大猩猩）。基于猴免疫缺陷病毒（SIV）感染猕猴的替代模型系统是可用的，但不能重现 HIV-1 感染和疾病的所有方面。含有人类免疫系统的人类化小鼠可用于研究 HIV-1，但迄今为止，关于早期事件和免疫反应的信息有限。在这里，我们描述了对 HIV-1 的早期免疫反应，并证明了细胞内固有先天免疫的抑制。此外，我们表明 HIV-1 感染与血液和淋巴器官中的先天免疫反应以不同的方式相互作用。
