Regulation of P-glycoprotein by human immunodeficiency virus-1 in primary cultures of human fetal astrocytes

✍ Scribed by Tamima Ashraf; Patrick T. Ronaldson; Yuri Persidsky; Reina Bendayan

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 760 KB
• Volume: 89
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22720

✦ Synopsis

Abstract

P‐glycoprotein (P‐gp), a drug efflux pump, is known to alter the bioavailability of antiretroviral drugs at several sites, including the brain. We have previously shown that human immunodeficiency virus‐1 (HIV‐1) glycoprotein 120 (gp120) induces proinflammatory cytokine secretion and decreases P‐gp functional expression in rat astrocytes, a cellular reservoir of HIV‐1. However, whether P‐gp is regulated in a similar way in human astrocytes is unknown. This study investigates the regulation of P‐gp in an in vitro model of gp120‐triggered human fetal astrocytes (HFAs). In this system, elevated levels of interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor‐α were detected in culture supernatants. Pretreatment with CCR5 neutralizing antibody attenuated cytokine secretion, suggesting that gp120‐CCR5 interaction mediated cytokine production. Treatment with gp120 (R5‐tropic) resulted in reduced P‐gp expression (64%) and function as determined by increased (1.6‐fold) cellular accumulation of [^3^H]digoxin, a P‐gp substrate. Exposure to R5 or R5/X4‐tropic viral isolates led to a downregulation in P‐gp expression (75% or 90%, respectively), and treatment with IL‐6 also showed lower P‐gp expression (50%). Moreover, IL‐6 neutralizing antibody blocked gp120‐mediated P‐gp downregulation, suggesting that IL‐6 is a key modulator of P‐gp. Gp120‐ or IL‐6‐mediated downregulation of P‐gp was attenuated by SN50 (a nuclear factor‐κB [NF‐κB] inhibitor), suggesting involvement of NF‐κB signaling in P‐gp regulation. Our results suggest that, similarly to the case with rodent astrocytes, pathophysiological stressors associated with brain HIV‐1 infection have a downregulatory effect on P‐gp functional expression in human astrocytes, which may ultimately result in altered antiretroviral drug accumulation within brain parenchyma. © 2011 Wiley‐Liss, Inc.