128. Selective presence of proinflammatory mediators in the hippocampus of HIV-1 transgenic rats

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144). HIV-1 transgene expression in vivo increases the expression of miR-144 in the alveolar epithelium, and this can be replicated by direct exposure of naïve primary AECs to either Tat or gp120 ex vivo. Further, treating naïve primary AECs with a miR-144 mimic decreased the expression and activity of Nrf2 and inhibited their barrier formation. In contrast, treatment with a miR-144 antagomir increased the expression and activity of Nrf2 and improved barrier function in primary AECs isolated from HIV-1 transgenic rats. Importantly, either delivering the miR-144 antagomir intratracheally, or directly activating Nrf2 by dietary treatment with PB123, increased Nrf2 expression and barrier formation in HIV-1 transgenic rat AECs. This study provides new experimental evidence that HIV-induced inhibition of Nrf2 and consequent AEC barrier dysfunction are mediated via miR-144, and that these pathophysiological effects can be mitigated in vivo by either directly antagonizing miR-144 or activating Nrf2. Our findings suggest that targeting the inhibition of Nrf2 in individuals living with HIV could enhance their lung health and decrease the lung-specific morbidity and mortality that persists despite antiretroviral therapy.

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214 Increased expression of Suppressor of Cytokine Signaling-1 (SOCS-1) by HIV-1 transgenic rats: A mechanism for dysregulated T helper-1 responses

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/01.qai.0000351170.33596.e9 ◽

2009 ◽

Vol 51 ◽

pp. 1

Author(s):

William Reid

Keyword(s):

Cytokine Signaling ◽

T Helper ◽

T Helper 1 ◽

Suppressor Of Cytokine Signaling ◽

Transgenic Rats ◽

Hiv 1

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HIV-1 transgenic rats develop T cell abnormalities

Virology ◽

10.1016/j.virol.2003.12.010 ◽

2004 ◽

Vol 321 (1) ◽

pp. 111-119 ◽

Cited By ~ 23

Author(s):

William Reid ◽

Sayed Abdelwahab ◽

Mariola Sadowska ◽

David Huso ◽

Ashley Neal ◽

...

Keyword(s):

T Cell ◽

Transgenic Rats ◽

Hiv 1

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Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00288.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. L267-L277 ◽

Cited By ~ 39

Author(s):

Xian Fan ◽

Bashar S. Staitieh ◽

J. Spencer Jensen ◽

Kara J. Mould ◽

Jared A. Greenberg ◽

...

Keyword(s):

Oxidative Stress ◽

Alveolar Epithelium ◽

Antioxidant Response ◽

Antioxidant Defenses ◽

Epithelial Barrier ◽

Transgenic Rats ◽

Alveolar Epithelial ◽

Related Proteins ◽

Hiv 1 ◽

Junction Proteins

The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.

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