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HIV-1 Vpr enhances PPAR?/?-mediated transcription, increases PDK4 expression, and reduces PDC activity.

ABSTRACT: HIV infection and its therapy are associated with disorders of lipid metabolism and bioenergetics. Previous work has suggested that viral protein R (Vpr) may contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients. In adipocytes, Vpr suppresses mRNA expression of peroxisomal proliferator-activating receptor-? (PPAR?)-responsive genes and inhibits differentiation. We investigated whether Vpr might interact with PPAR?/? and influence its transcriptional activity. In the presence of PPAR?/?, Vpr induced a 3.3-fold increase in PPAR response element-driven transcriptional activity, a 1.9-fold increase in pyruvate dehydrogenase kinase 4 (PDK4) protein expression, and a 1.6-fold increase in the phosphorylated pyruvate dehydrogenase subunit E1? leading to a 47% decrease in the activity of the pyruvate dehydrogenase complex in HepG2 cells. PPAR?/? knockdown attenuated Vpr-induced enhancement of endogenous PPAR?/?-responsive PDK4 mRNA expression. Vpr induced a 1.3-fold increase in mRNA expression of both carnitine palmitoyltransferase I (CPT1) and acetyl-coenzyme A acyltransferase 2 (ACAA2) and doubled the activity of ?-hydroxylacyl coenzyme A dehydrogenase (HADH). Vpr physically interacted with the ligand-binding domain of PPAR?/? in vitro and in vivo. Consistent with a role in energy expenditure, Vpr increased state-3 respiration in isolated mitochondria (1.16-fold) and basal oxygen consumption rate in intact HepG2 cells (1.2-fold) in an etomoxir-sensitive manner, indicating that the oxygen consumption rate increase is ?-oxidation-dependent. The effects of Vpr on PPAR response element activation, pyruvate dehydrogenase complex activity, and ?-oxidation were reversed by specific PPAR?/? antagonists. These results support the hypothesis that Vpr contributes to impaired energy metabolism and increased energy expenditure in HIV patients.

SUBMITTER: Shrivastav S

PROVIDER: S-EPMC3753422 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity.

Shrivastav Shashi S Zhang Liyan L Okamoto Koji K Lee Hewang H Lagranha Claudia C Abe Yoshifusa Y Balasubramanyam Ashok A Lopaschuk Gary D GD Kino Tomoshige T Kopp Jeffrey B JB

Molecular endocrinology (Baltimore, Md.) 20130710 9

HIV infection and its therapy are associated with disorders of lipid metabolism and bioenergetics. Previous work has suggested that viral protein R (Vpr) may contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients. In adipocytes, Vpr suppresses mRNA expression of peroxisomal proliferator-activating receptor-γ (PPARγ)-responsive genes and inhibits differentiation. We investigated whether Vpr might interact with PPARβ/δ and influence its transcript ...[more]

PMID: 23842279

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Project description:UnlabelledThe HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G2 cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-?B activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replication in vivo.ImportanceThe role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation.

Dataset Information

HIV-1 Vpr enhances PPAR?/?-mediated transcription, increases PDK4 expression, and reduces PDC activity.

Publications

HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity.

Similar Datasets

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