UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California.
Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
AIDS Res Hum Retroviruses. 2020 Feb;36(2):122-130. doi: 10.1089/AID.2019.0160. Epub 2019 Nov 4.
HIV-1-induced cytopathicity of thymocytes is a major cause of reduced peripheral T cells and rapid disease progression observed in HIV-1-infected infants. Understanding the virulence factors responsible for thymocyte depletion has paramount importance in addressing the pathogenesis of disease progression in children. In this study, thymocyte depletion was analyzed following infection with two primary CXCR4-tropic HIV-1 pediatric isolates (PI), PI-2 and PI-2.1, which were serially derived from an -infected infant. Although highly similar to each other, PI-2 showed markedly decreased thymocyte depletion compared with PI-2.1. Further analysis showed a novel deletion in the Nef protein (NefΔK7S) of PI-2, which was absent in PI-2.1. This deletion inhibited Nef-mediated major histocompatibility complex class I (MHC-I) downregulation in infected thymocytes and ; in contrast, the mutated Nef continued to downregulate CD4 surface expression These results suggest that HIV-1 Nef contributes to thymic damage in infants through selective functions.
HIV-1 诱导的胸腺细胞病变是导致 HIV-1 感染婴儿外周 T 细胞减少和疾病快速进展的主要原因。了解导致胸腺细胞耗竭的毒力因子对于阐明儿童疾病进展的发病机制至关重要。在这项研究中，我们分析了感染两种主要的 CXCR4 嗜性 HIV-1 儿科分离株（PI）PI-2 和 PI-2.1 后胸腺细胞的耗竭情况，这两种分离株是从一名受感染的婴儿中连续衍生而来的。尽管它们彼此非常相似，但与 PI-2.1 相比，PI-2 显示出明显减少的胸腺细胞耗竭。进一步的分析表明，PI-2 的 Nef 蛋白（NefΔK7S）中存在一个新的缺失，而 PI-2.1 中则没有这个缺失。这个缺失抑制了感染的胸腺细胞中 Nef 介导的主要组织相容性复合体 I（MHC-I）下调，而突变的 Nef 继续下调 CD4 表面表达。这些结果表明，HIV-1 Nef 通过选择性功能导致婴儿的胸腺损伤。
