{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:25:32Z","timestamp":1761845132916,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P50HL118006","R01HL125005"],"award-info":[{"award-number":["P50HL118006","R01HL125005"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["U54MD007597"],"award-info":[{"award-number":["U54MD007597"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P30AI087714"],"award-info":[{"award-number":["P30AI087714"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide (LPS) induced significantly higher levels of neutrophil infiltration in the lungs compared to wild-type (WT) mice. In WT mice, the initial neutrophil infiltration was followed by macrophage infiltration and fast resolution of leukocytes infiltration. In HIV-Tg mice, resolution of lung infiltration by both neutrophils and macrophages was significantly delayed, with macrophages accumulating in the lumen of lung capillaries resulting in a 45% higher rate of mortality. Trans-endothelial migration of HIV-Tg macrophages was significantly reduced in vitro and this reduction correlated with lower HIV-1 gene expression. HIV-1 transcription inhibitor, 1E7-03, enhanced trans-endothelial migration of HIV-Tg macrophages in vitro, decreased lung neutrophil infiltration in vivo, and increased lung macrophage levels in HIV-Tg mice. Moreover, 1E7-03 reduced levels of inflammatory IL-6 cytokine, improved bleeding score and decreased lung injury. Together this indicates that inhibitors of HIV-1 transcription can correct abnormal dynamics of leukocyte infiltration in HIV-Tg, pointing to the utility of transcription inhibition in the treatment of HIV-1 associated chronic lung disease.<\/jats:p>","DOI":"10.3390\/v12020204","type":"journal-article","created":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T10:09:57Z","timestamp":1581674997000},"page":"204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes\u2019 Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Marina","family":"Jerebtsova","sequence":"first","affiliation":[{"name":"Department of Microbiology, College of Medicine, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asrar","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Center for Sickle Cell Disease, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomei","family":"Niu","sequence":"additional","affiliation":[{"name":"Center for Sickle Cell Disease, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ornela","family":"Rutagarama","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0744-7887","authenticated-orcid":false,"given":"Sergei","family":"Nekhai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, Howard University, Washington, DC 20059, USA"},{"name":"Center for Sickle Cell Disease, Howard University, Washington, DC 20059, USA"},{"name":"Department of Medicine, Howard University, Washington, DC 20059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1056\/NEJMoa030218","article-title":"Data Collection on Adverse Events of Anti, H.I.V.D.S.G., Combination antiretroviral therapy and the risk of myocardial infarction","volume":"349","author":"Sabin","year":"2003","journal-title":"New Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1097\/QAD.0b013e3282efad32","article-title":"Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection","volume":"21","author":"Wand","year":"2007","journal-title":"Aids"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/resp.12385","article-title":"Lung function abnormalities in HIV-infected adults and children","volume":"20","author":"Calligaro","year":"2015","journal-title":"Respirology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1513\/pats.201006-045WR","article-title":"HIV and chronic obstructive pulmonary disease: Is it worse and why?","volume":"8","author":"Morris","year":"2011","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1513\/pats.201009-059WR","article-title":"HIV-associated lung infections and complications in the era of combination antiretroviral therapy","volume":"8","author":"Crothers","year":"2011","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Agusti, A., Edwards, L.D., Rennard, S.I., MacNee, W., Tal-Singer, R., Miller, B.E., Vestbo, J., Lomas, D.A., Calverley, P.M., and Wouters, E. (2012). Persistent systemic inflammation is associated with poor clinical outcomes in COPD: A novel phenotype. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037483"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0140-6736(11)60968-9","article-title":"Chronic obstructive pulmonary disease","volume":"379","author":"Decramer","year":"2012","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.7326\/0003-4819-132-5-200003070-00006","article-title":"Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers","volume":"132","author":"Diaz","year":"2000","journal-title":"Ann. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.cyto.2013.09.010","article-title":"The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma","volume":"64","author":"Pappas","year":"2013","journal-title":"Cytokine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1586\/1744666X.2013.851347","article-title":"Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease","volume":"9","author":"Meijer","year":"2013","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.intimp.2013.05.035","article-title":"Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: The neutrophil as an immunotherapeutic target","volume":"17","author":"Stockley","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1378\/chest.14-0543","article-title":"Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4","volume":"146","author":"Attia","year":"2014","journal-title":"Chest"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1097\/QAD.0000000000000471","article-title":"Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort","volume":"28","author":"Fitzpatrick","year":"2014","journal-title":"Aids"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2018.01.004","article-title":"Correlation of severity of chronic obstructive pulmonary disease with potential biomarkers","volume":"196","author":"Singh","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1385\/IR:36:1:175","article-title":"Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome","volume":"36","author":"Norris","year":"2006","journal-title":"Immunol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1089\/vim.2013.0130","article-title":"The complexity of HIV persistence and pathogenesis in the lung under antiretroviral therapy: Challenges beyond AIDS","volume":"27","author":"Almodovar","year":"2014","journal-title":"Viral Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11378","DOI":"10.1073\/pnas.91.24.11378","article-title":"Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop","volume":"91","author":"Itescu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"247","DOI":"10.2217\/hiv.10.5","article-title":"Measurement of antiretroviral drugs in the lungs of HIV-infected patients","volume":"4","author":"Twigg","year":"2010","journal-title":"HIV Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.4049\/jimmunol.149.4.1462","article-title":"Role of cytokines in alveolar macrophage accessory cell function in HIV-infected individuals","volume":"149","author":"Twigg","year":"1992","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.4049\/jimmunol.150.3.1019","article-title":"Activation of alveolar macrophages in asymptomatic HIV-infected individuals","volume":"150","author":"Buhl","year":"1993","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1378\/chest.88.3.352","article-title":"Pulmonary cell populations in the immunosuppressed patient. Bronchoalveolar lavage findings during episodes of pneumonitis","volume":"88","author":"White","year":"1985","journal-title":"Chest"},{"key":"ref_22","first-page":"786","article-title":"Cellular and T-lymphocyte subpopulation profiles in bronchoalveolar lavage fluid from patients with acquired immunodeficiency syndrome and pneumonitis","volume":"130","author":"Wallace","year":"1984","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/prd.12034","article-title":"Natural resolution of inflammation","volume":"63","author":"Freire","year":"2013","journal-title":"Periodontol. 2000"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1172\/JCI119525","article-title":"Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression","volume":"100","author":"Bruggeman","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1073\/pnas.89.5.1577","article-title":"Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes","volume":"89","author":"Kopp","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/ki.1994.331","article-title":"bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice","volume":"46","author":"Ray","year":"1994","journal-title":"Kidney Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1046\/j.1523-1755.2000.00152.x","article-title":"HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy","volume":"58","author":"Barisoni","year":"2000","journal-title":"Kidney Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"L811-9","DOI":"10.1152\/ajplung.00468.2005","article-title":"HIV-1-induced pulmonary oxidative and nitrosative stress: Exacerbated response to endotoxin administration in HIV-1 transgenic mouse model","volume":"291","author":"Jacob","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1006\/viro.1994.1416","article-title":"Patterns of HIV-1 mRNA expression in transgenic mice are tissue-dependent","volume":"202","author":"Bruggeman","year":"1994","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1089\/aid.1989.5.421","article-title":"The human immunodeficiency virus long terminal repeat is preferentially expressed in Langerhans cells in transgenic mice","volume":"5","author":"Leonard","year":"1989","journal-title":"Aids Res. Hum. Retrovir."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1186\/s12974-018-1322-2","article-title":"Adult neurogenic deficits in HIV-1 Tg26 transgenic mice","volume":"15","author":"Putatunda","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.1111\/bph.12863","article-title":"1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription","volume":"171","author":"Ammosova","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H743-50","DOI":"10.1152\/ajpheart.00969.2006","article-title":"A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice","volume":"292","author":"Jerebtsova","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1164\/ajrccm.161.1.9902089","article-title":"Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide","volume":"161","author":"Heremans","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_35","first-page":"233","article-title":"Vascular permeability factor\/vascular endothelial growth factor: A multifunctional angiogenic cytokine","volume":"79","author":"Brown","year":"1997","journal-title":"Exs"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.2174\/1568026616666150930121157","article-title":"Vascular Biomarkers in Asthma and COPD","volume":"16","author":"Bakakos","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.freeradbiomed.2016.04.009","article-title":"Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration","volume":"96","author":"Kwon","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00467-011-2001-z","article-title":"Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice","volume":"27","author":"Mattison","year":"2012","journal-title":"Pediatric Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"76749","DOI":"10.18632\/oncotarget.19999","article-title":"Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03","volume":"8","author":"Lin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1182\/blood-2014-08-596775","article-title":"HIV-1 reprograms the migration of macrophages","volume":"125","author":"Verollet","year":"2015","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1513\/pats.2009-047WS","article-title":"An official ATS workshop report: Emerging issues and current controversies in HIV-associated pulmonary diseases","volume":"8","author":"Morris","year":"2011","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000163649","article-title":"Secretory repertoire of HIV-infected human monocytes\/macrophages","volume":"59","author":"Esser","year":"1991","journal-title":"Pathobiol.: J. Immunopathol. Mol. Cell. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1097\/COH.0b013e3283497203","article-title":"Macrophages and HIV-1","volume":"6","author":"Booiman","year":"2011","journal-title":"Curr. Opin. Hiv Aids"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6388","DOI":"10.4049\/jimmunol.168.12.6388","article-title":"Inhibition of CXCR4-tropic HIV-1 infection by lipopolysaccharide: Evidence of different mechanisms in macrophages and T lymphocytes","volume":"168","author":"Verani","year":"2002","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.clim.2008.01.007","article-title":"LPS reduces HIV-1 replication in primary human macrophages partly through an endogenous production of type I interferons","volume":"127","author":"Simard","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"L1245-52","DOI":"10.1152\/ajplung.00453.2001","article-title":"Role of resident alveolar macrophages in leukocyte traffic into the alveolar air space of intact mice","volume":"282","author":"Maus","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.immuni.2010.11.011","article-title":"Neutrophils, from marrow to microbes","volume":"33","author":"Borregaard","year":"2010","journal-title":"Immunity"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nri1785","article-title":"Neutrophils and immunity: Challenges and opportunities","volume":"6","author":"Nathan","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1086\/314662","article-title":"Enhanced production of tumor necrosis factor-alpha and interleukin-6 due to prolonged response to lipopolysaccharide in human macrophages infected in vitro with human immunodeficiency virus type 1","volume":"179","author":"Bergamini","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1055\/s-2000-13214","article-title":"LPS and cytokine-activated endothelium","volume":"26","author":"Bierhaus","year":"2000","journal-title":"Semin. Thromb. Hemost."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/2\/204\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:57:12Z","timestamp":1760173032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/2\/204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,12]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["v12020204"],"URL":"https:\/\/doi.org\/10.3390\/v12020204","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2020,2,12]]}}}