Despite anti-retroviral therapy, HIV-1 infection increases the risk of pneumonia and causes oxidative stress and defective alveolar macrophage (AM) immune function. We have previously determined that HIV-1 proteins inhibit antioxidant defenses and impair AM phagocytosis by suppressing nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Given its known effects on Nrf2, we hypothesize miR-144 mediates the HIV-1 induced suppression of Nrf2.
Primary AMs isolated from HIV-1 transgenic (HIV-1 Tg) rats and wild type littermates (WT) as well as human monocyte-derived macrophages (MDMs) infected ex vivo with HIV-1 were used. We modulated miR-144 expression using a miR-144 mimic or an inhibitor to assay its effects on Nrf2/ARE activity and AM functions in vitro and in vivo.
MiR-144 expression was increased in AMs from HIV-1 Tg rats and in HIV-1-infected human MDMs compared to cells from WT rats and non-infected human MDMs, respectively. Increasing miR-144 with a miR-144 mimic inhibited the expression of Nrf2 and its downstream effectors in WT rat macrophages and consequently impaired their bacterial phagocytic capacity and H2O2 scavenging ability. These effects on Nrf2 expression and AM function were reversed by antagonizing miR-144 ex vivo or in the airways of HIV-1 Tg rats in vivo, but this protection was abrogated by silencing Nrf2 expression.
Our results suggest that inhibiting miR-144 or interfering with its deleterious effects on Nrf2 attenuates HIV-1-mediated AM immune dysfunction and improves lung health in individuals with HIV.
Key Indexing Terms
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to The American Journal of the Medical Sciences
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Abnormalities in host defense associated with HIV infection.Clin Chest Med. 2013; 34: 143-153
- Noninfectious pulmonary complications of human immunodeficiency virus infection.Am J Med Sci. 2014; 348: 502-511
UNAIDS. Global HIV & AIDS statistics - 2019 fact sheet. 2019.
- Pulmonary complications of HIV infection: autopsy findings.Chest. 1998; 113: 1225-1229
- Impact of highly active antiretroviral therapy on incidence and management of human immunodeficiency virus-related opportunistic infections.J Antimicrob Chemother. 2004; 54: 849-853
- Anti-retroviral therapy is associated with decreased alveolar glutathione levels even in healthy HIV-infected individuals.PLoS ONE. 2014; 9: e88630
- Healthy HIV-1-infected individuals on highly active antiretroviral therapy harbor HIV-1 in their alveolar macrophages.AIDS Res Hum Retroviruses. 2015; 31: 64-70
- HIV-1-transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis.Am J Respir Cell Mol Biol. 2008; 39: 218-226
- HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction.AIDS Res Ther. 2009; 6: 1
- HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages.J Leukoc Biol. 2017; 102: 517-525
- Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats.Am J Physiol Lung Cell Mol Physiol. 2013; 305: L267-L277
- MicroRNAs in development and disease.Physiol Rev. 2011; 91: 827-887
- Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells.PLoS ONE. 2012; 7: e51111
- Epigenetic regulation of Keap1-Nrf2 signaling.Free Radic Biol Med. 2015; 88: 337-349
- microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease.Blood. 2010; 116: 4338-4348
- MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats.Am J Physiol Cell Physiol. 2019; 317: C390-C3C7
- Pneumonia due to Pseudomonas aeruginosa: part I: epidemiology, clinical diagnosis, and source.Chest. 2011; 139: 909-919
- Clinical course, prognostic factors, and outcome prediction for HIV patients in the ICU. The PIP (Pulmonary complications, ICU support, and prognostic factors in hospitalized patients with HIV) study.Chest. 2000; 118: 138-145
- Bacterial pneumonia in hospitalized patients with HIV infection: the Pulmonary Complications, ICU Support, and Prognostic Factors of Hospitalized Patients with HIV (PIP) Study.Chest. 2000; 117: 1017-1022
- Aspergillus fumigatus, Pneumocystis jiroveci, Klebsiella pneumoniae & Mycoplasma fermentans co-infection in a HIV infected patient with respiratory conditions from Southern India.Indian J Med Res. 2006; 123: 181-184
- Excess mortality due to pneumonia or influenza during influenza seasons among persons with acquired immunodeficiency syndrome.Arch Intern Med. 2001; 161: 441-446
- Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group.N Engl J Med. 1995; 333: 845-851
- Current insights into the biology and pathogenesis of Pneumocystis pneumonia.Nat Rev Microbiol. 2007; 5: 298-308
- Pulmonary Innate Immune Dysfunction in Human Immunodeficiency Virus.Am J Respir Cell Mol Biol. 2017; 56: 563-567
- Permanent declines in pulmonary function following pneumonia in human immunodeficiency virus-infected persons. The Pulmonary Complications of HIV Infection Study Group.Am J Respir Crit Care Med. 2000; 162: 612-616
- Nrf2 regulates PU.1 expression and activity in the alveolar macrophage.Am J Physiol Lung Cell Mol Physiol. 2015; 308: L1086-L1093
- Increased COPD among HIV-positive compared to HIV-negative veterans.Chest. 2006; 130: 1326-1333
- Chronic obstructive pulmonary disease in patients who have HIV infection.Clin Chest Med. 2007; 28 (vi): 575-587
- Human immunodeficiency virus-associated obstructive lung diseases.Clin Chest Med. 2013; 34: 273-282
- Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers.Ann Intern Med. 2000; 132: 369-372
- MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.Nature reviews Drug discovery. 2017; 16: 203-222
- Targeting MicroRNA Function in Respiratory Diseases: mini-Review.Front Physiol. 2016; 7: 21
- MicroRNAs in respiratory disease. A clinician's overview.Ann Am Thorac Soc. 2014; 11: 1277-1285
- MicroRNAs as biomarkers of acute lung injury.Ann Transl Med. 2018; 6: 34
- MicroRNAs and HIV-1: complex interactions.J Biol Chem. 2012; 287: 40884-40890
- Are microRNAs Important Players in HIV-1 Infection? An update.Viruses. 2018; 10: 110
- MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease.Exp Hematol. 2019; 70 (85-96 e5)
- miR-144 regulates oxidative stress tolerance of thalassemic erythroid cell via targeting NRF2.Ann Hematol. 2019; 98: 2045-2052
- Enforced miR-144-3p expression as a non-invasive biomarker for the acute myeloid leukemia patients mainly by targeting NRF2.Clin Lab. 2017; 63: 679-687
- MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism.Breast Cancer Res Treat. 2011; 129: 983-991
- miR-144 attenuates the host response to influenza virus by targeting the TRAF6-IRF7 signaling axis.PLoS Pathog. 2017; 13e1006305
- HIV induced nitric oxide and lipid peroxidation, influences neonatal birthweight in a South African population.Environ Int. 2018; 121: 1-12
Published online: July 20, 2020
Accepted: July 17, 2020
Received: January 17, 2020
The authors declare no conflicts of interests.
Funding for this work was provided by R01HL125042 (DMG), R01AI150475 (PS) and K08 AA024512 (BSS).
© 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.