Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States.
Respiratory Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, NM, United States.
Front Cell Infect Microbiol. 2021 Feb 4;10:612360. doi: 10.3389/fcimb.2020.612360. eCollection 2020.
The role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable.
Normal human bronchial epithelial cells (NHBEs) grown on air-liquid interface were infected with X4-tropic HIV-1 and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining.
NHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1 in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH.
肺上皮细胞在 HIV-1 相关肺部合并症中的作用尚不清楚，而治愈 HIV 的主要障碍是 HIV 潜伏储库在 HIV 感染者（PLWH）中的持续存在。联合抗逆转录病毒疗法的出现极大地延长了患者的寿命；然而，PLWH 慢性肺部疾病的发病率显著更高。肺上皮细胞协调呼吸免疫反应，这些细胞是否被 HIV-1 有效感染仍存在争议。
在气液界面上培养的正常人支气管上皮细胞（NHBEs）感染 X4 嗜性 HIV-1，并使用潜伏逆转剂（LRAs）检测潜伏。测试了 CD4 和 CXCR4 HIV 核心受体在 NHBEs 中的作用，并使用 DNA 测序分析来分析 HIV 前病毒基因、Alu-HIVgag-pol、HIV-nef 和 HIV-LTR 的基因组整合。通过 FISH 分析 HIV-gag-pol RNA 和上皮细胞特异性免疫染色分析 HIV 感染的人类和 SHIV 感染的猕猴的肺上皮组织。
NHBEs 表达的 CD4 和 CXCR4 水平高于 A549 细胞。NHBEs 以 CXCR4/CD4 依赖的方式被 X4 嗜性 HIV-1 从基底外侧感染，但不能从顶侧感染，导致 HIV-p24 抗原产生；然而，IL-13 处理诱导 NHBEs 表达 CCR5。在 cART 存在的情况下，HIV-1 诱导 HIV 前病毒的潜伏和整合到细胞 DNA 中，LRAs（内毒素/伏立诺他）可挽救这种潜伏。此外，HIV 感染的人类和 SHIV 感染的猕猴的肺上皮细胞含有 HIV 特异性 RNA 转录本。因此，肺上皮细胞是 HIV-1 的靶标，可能成为潜在的 HIV 储库，从而导致 PLWH 的呼吸合并症。
