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

Abstract

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.

Oxygen Levels Affect Macrophage HIV-1 Gene Expression and Delay Resolution of Inflammation in HIV-Tg Mice

“…In contrast, lung neutrophil (polymorphonuclear cells PMNC) levels were significantly elevated in HIV-Tg mice. Additionally, we observed the delayed resolution of both Mφ and PMNC lung infiltration in HIV-Tg mice that resulted in increased mortality [9]. Moreover, we demonstrated that HIV-1 expression in Mφ was associated with altered trans-endothelial Mφ migration in vitro and in mouse model.…”

“…The accumulation of macrophages in lung capillaries may be explained by impaired Mφ trans-endothelial migration. Previously we demonstrated that trans-endothelial migration of HIV-Tg macrophages was reduced compared to WT macrophages in vitro, and inhibition of HIV-1 gene expression restored the ability of Mφs to migrate through endothelial cells [9].…”

“…A Boyden chamber consists of a lower and an upper chamber, separated by polycarbonated membrane. Murine lung endothelial cell line (MLEC) was generated as described [9]. Endothelial cells were seeded on the membrane inserts and incubated at 21% O 2 until the monolayers were formed.…”

“…We have recently demonstrated impaired dynamics of LPS-induced lung leukocyte infiltration and the resolution of inflammation in an HIV-transgenic (HIV-Tg) mouse model [9]. HIV-Tg mice carry non-replicating and non-infectious HIV-1 transgene with the deletion of gag and pol genes.…”

“…In the pathogen-free animal facility, HIV-Tg mice do not develop intestinal microbial translocation. Intraperitoneal injection of E.coli endotoxin (LPS) was used to model gut microbial products' translocation [9]. After LPS administration, HIV-Tg mice had significantly lower lung macrophage (Mφ) levels compared to wild type (WT) during the early timepoints of immune system activation.…”