HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells

BackgroundThe 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.MethodsNormal human bronchial epithelial cells (NHBEs) grown on air–liquid interface were infected with X4-tropic HIV-1LAV 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.Results and DiscussionNHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1LAV 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.

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Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

10.1101/2020.06.01.126821 ◽

2020 ◽

Author(s):

Dinesh Devadoss ◽

Shashi P. Singh ◽

Arpan Acharya ◽

Kieu Chinh Do ◽

Palsamy Periyasamy ◽

...

Keyword(s):

Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Lung Epithelial Cells ◽

People Living With Hiv ◽

Bronchial Epithelial ◽

Highly Active ◽

The People ◽

Lung Epithelial ◽

Latent Hiv ◽

Hiv 1

ABSTRACTIn the era of highly active anti-retroviral therapy (HAART), obstructive lung diseases (OLDs) are common among the people living with HIV (PLWH); however, the mechanism by which HIV induces OLDs is unclear. Although human bronchial epithelial cells (HBECs) express HIV coreceptors and are critical in regulating lung immune responses, their role in transmitting HIV remains unclear. Herein, we present evidence that HIV-1 infects normal HBECs and the viral DNA is integrated in the genome to establish the viral latency. To prove that HIV productively infects HBECs, we demonstrate: (a) along with CXCR4, HBECs express the HIV-receptor CD4, and are induced to express CCR5 by IL-13 treatment; (b) following infection with HIV, HBECs produce HIV-p24 and contain the latent HIV provirus, which is activated by endotoxin and/or vorinostat; (c) DNA from HIV-1 infected HBECs contains the HIV-specific gag and nef genes, along with Alu sequences, confirming the integration of HIV in the host DNA; (d) the lung epithelial cells of HIV-infected subjects and SHIV-infected cynomolgus macaques are positive for HIV-specific transcripts. Thus, these studies suggest that HIV establishes latency in lung epithelial cells, making them potential HIV reservoirs. The long-living lung epithelial cells, activated by commonly encountered lung infections, might represent an ideal HIV target/reservoir, contributing to OLDs and other HIV-associated lung comorbidities.

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15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00036.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. L196-L203 ◽

Cited By ~ 28

Author(s):

Cheng Liu ◽

Dawei Xu ◽

Li Liu ◽

Frida Schain ◽

Åsa Brunnström ◽

...

Keyword(s):

Epithelial Cells ◽

Human Lung ◽

A549 Cells ◽

Airway Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Lung Epithelial Cells ◽

Epithelial Cell Line ◽

Chronic Obstructive ◽

Bronchial Epithelial ◽

Lung Epithelial

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1α, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.

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Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

Scientific Reports ◽

10.1038/s41598-020-73752-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Akina Kawara ◽

Ryo Mizuta ◽

Masayoshi Fujisawa ◽

Toshihiro Ito ◽

Chunning Li ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Tissue Repair ◽

Bronchial Epithelial Cells ◽

Lung Epithelial Cells ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Clara Cells ◽

Bronchial Epithelial ◽

Lung Epithelial

Abstract The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

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