Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology
Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology
复制标题
DOI：
10.1128/jvi.00372-19
复制
发表时间：
2019-09-01
影响因子：
5.4
通讯作者：
Manuzak, Jennifer A.
中科院分区：
文献类型：
--
作者：
Bar, Katharine J.;Coronado, Ernesto;Manuzak, Jennifer A.
猿猴-人类免疫缺陷病毒（SHIV）已被用来测试疫苗功效并表征病毒传播和发病机制。然而，目前可用的大多数 SHIV 都具有显着的局限性，因为它们是使用来自长期 HIV 感染者或不常见的 HIV 亚型的序列开发的，或者通过在体外或体内连续传代工程病毒来针对猕猴模型进行优化。最近，一种新开发的 SHIV，SHIV.C.CH505.375H.dCT (SHIV.CH505)，它整合了来自传播/创始人 HIV-1 C 亚型毒株的 vpu-env (gp140) 序列，被证明保留了主要 HIV-1 毒株的属性。然而，对该病毒感染引起的免疫病理学的全面分析，特别是在肠粘膜等关键组织区室中，尚未完成。在这项研究中，我们评估了恒河猴中 SHIV.CH505 的病毒动力学和免疫病理学。与之前的研究结果一致，我们发现 SHIV.CH505 能够在恒河猴中有效感染和复制，从而产生与致病性 SIV 和 HIV 感染相似的外周病毒动力学。此外，我们观察到粘膜组织中CCR5（+）和CCR6（+）CD4（+）T细胞显着且持续的耗竭，产生Th17细胞相关细胞因子的CD4（+）T细胞减少，CD8（+）T细胞功能障碍以及B细胞和先天免疫细胞功能的改变，表明SHIV.CH505引发了SIV/HIV感染的典型肠道免疫病理学。这些发现表明，SHIV.CH505 概括了人类 HIV-1 感染的早期病毒复制动态和免疫发病机制，因此可以作为 HIV-1 发病机制、治疗和预防研究的新模型。 重要性 嵌合 SHIV 的开发有助于增进我们对 HIV-宿主相互作用的理解，并允许对新疗法进行体内测试。然而，目前许多SHIV具有明显的缺陷，无法充分反映SIV原发株和HIV毒株的特征。在这里，我们利用恒河猴来定义最近开发的 SHIV.CH505 的免疫发病机制，该药物的设计没有以前 SHIV 的许多限制。我们观察到，SHIV.CH505 感染导致的外周病毒动力学和粘膜免疫发病机制与致病性 Sly 和 HIV 引起的相似。总体而言，这些数据证明了 SHIV.CH505 作为 SIV/HIV 感染的有效模型以及可用于未来研究（包括新疗法或预防策略的临床前测试）的重要工具的价值。
Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5(+) and CCR6(+) CD4(+) T cells in mucosal tissues, decreases in CD4(+) T cells producing Th17 cell-associated cytokines, CD8(+) T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research.IMPORTANCE The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic Sly and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.