Abstract
We determined if HIV-1 expression in transgenic (HIV-1-Tg) rats enhanced hepatic genomic changes related to oxidative/nitrosative stress and lipogenesis during cART-treatment, and assessed effects of Mg-supplementation. A clinically used cART (atazanavir-ritonavir+Truvada) was given orally to control and HIV-1-Tg rats (18 weeks) with normal or 6-fold dietary-Mg. Oxidative/nitrosative and lipogenic genes were determined by real-time RT-PCR. cART induced a 4-fold upregulation of sterol regulatory element-binding protein-1 (SREBP-1) in HIV-1-Tg-rats, but not in controls; Tg rats displayed a 2.5-fold higher expression. Both were completely prevented by Mg-supplementation. Nrf2 (Nuclear erythroid-derived factor 2), a master transcription factor controlling redox homeostasis, was down-regulated 50% in HIV-Tg rats, and reduced further to 25% in Tg+cART-rats. Two downstream antioxidant genes, heme oxygenase-1(HmOX1) and Glutathione-S-transferase(GST), were elevated in HIV-Tg alone but were suppressed by cART treatment. Decreased Nrf2 in Tg±cART were normalized by Mg-supplementation along with the reversal of altered HmOX1 and GST expression. Concomitantly, iNOS (inducible nitric oxide synthase) was upregulated 2-fold in Tg+cART rats, which was reversed by Mg-supplementation. In parallel, cART-treatment led to substantial increases in plasma 8-isoprostane, nitrotyrosine, and RBC-GSSG (oxidized glutathione) levels in HIV-1-Tg rats; all indices of oxidative/nitrosative stress were suppressed by Mg-supplementation. Both plasma triglyceride and cholesterol levels were elevated in Tg+cART rats, but were lowered by Mg-supplementation. Thus, the synergistic effects of cART and HIV-1 expression on lipogenic and oxidative/nitrosative effects were revealed at the genomic and biochemical levels. Down-regulation of Nrf2 in the Tg+cART rats suggested their antioxidant response was severely compromised; these abnormal metabolic and oxidative stress effects were effectively attenuated by Mg-supplementation at the genomic level.
Highlights
Acquired immunodeficiency syndrome (AIDS) caused by HIV-1 was first formally recognized in patients in the USA in 1981 [1]
In a recent concurrent study [8], by using an established HIV-1 transgenic (Tg) rat model we found that a clinically used combination anti-retroviral therapy (cART), consisting of Truvada (2 NRTIs) plus atazanavir-ritonavir (2 protease inhibitors (PI)), induced early oxidative stress resulting in cardiac dysfunction
The present study demonstrates the differential responses to cART administration between control and HIV-1 Tg rats and the impact of Mg-supplementation on expression of key genes related to oxidative/ nitrosative stress, systemic inflammation, and lipogenesis
Summary
Acquired immunodeficiency syndrome (AIDS) caused by HIV-1 was first formally recognized in patients in the USA in 1981 [1]. With the introduction of combination anti-retroviral therapy (cART) consisting of 2 nucleoside analog inhibitors (NRTIs) plus 2 protease inhibitors (PIs), HIV-1 replication in infected patients was dramatically reduced to the extent that HIV-1 infection has become a more manageable disease [4,5]. Along with the chronic use of NRTI—and PI-containing cART, significant side effects of oxidative/nitrosative stress, hyperlipidemia, and lipodystrophy occurred [6]; these side effects might contribute to the increased cardiovascular disease associated with chronic use of cART in HIV-1 patients [6,7]. In a recent concurrent study [8], by using an established HIV-1 transgenic (Tg) rat model we found that a clinically used cART, consisting of Truvada (2 NRTIs) plus atazanavir-ritonavir (2 PIs), induced early oxidative stress resulting in cardiac dysfunction. We focused at the molecular level, on key transcriptome changes related to lipogenesis and antioxidant/nitrosative responses
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