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HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice

1
Department of Microbiology, College of Medicine, Howard University, Washington, DC 20059, USA
2
Center for Sickle Cell Disease, Howard University, Washington, DC 20059, USA
3
Department of Medicine, Howard University, Washington, DC 20059, USA
*
Authors to whom correspondence should be addressed.
Viruses 2020, 12(2), 204; https://doi.org/10.3390/v12020204
Received: 28 October 2019 / Revised: 4 February 2020 / Accepted: 11 February 2020 / Published: 12 February 2020
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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.
Keywords: HIV-transgenic mice; non-infectious lung disease; transcriptional inhibitor; leukocyte dynamics HIV-transgenic mice; non-infectious lung disease; transcriptional inhibitor; leukocyte dynamics
MDPI and ACS Style

Jerebtsova, M.; Ahmad, A.; Niu, X.; Rutagarama, O.; Nekhai, S. HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice. Viruses 2020, 12, 204.

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