Effects Of HIV Proteins Research Articles

Tu2052 Acute Liver Torsion: A Rare Case of Abdominal Pain and Elevated Liver Transaminases

Background. Matrix proteins are essential in the HIV replication cycle. The HIV matrix protein p17 serves several functions in the viral replication cycle including the viral nuclear import at early stage of infection. In the late stage, p17 mediates the recruitment of the viral surface/transmembrane gp120/gp41 envelope protein complex into virions and targets Pr55Gag proteins to their assembly sites at the plasma membrane of infected cells. Members of the nuclear receptor superfamily exert their regulatory activity integrating regulatory effects exerted by nutrients with intermediate metabolism by positively and negatively regulating the expression of effector genes. We have previously demonstrated that HIV infection is associated with an altered expression of nuclear receptor transcriptome in human monocytes as well as that stimulation of these cells with p17 down-regulates the expression of FXR and PPARγ. Aims. To analyze the effect exerted by the HIV matrix protein p17 on nuclear receptor gene expression in HepG2 cells. Methods. Serum starved HepG2 cells were stimulated 18 hours with 2 μg/ml recombinant p17 protein. At the end of the stimulation total RNA was extracted, reverse-transcribed in cDNA and amplified using specific primers for 10 nuclear receptors. Relative mRNA expression of Fatty Acid Elongase (FAE) was also investigated. Results. HepG2 cells treated with the HIV matrix protein p17 expressed an altered pattern of nuclear receptors characterized by a profound down-regulation in the expression of PPARα, -β, -γ, RARα, RXR, LXRβ, FXR, SHP, PXR and GR. Of interest, the deregulated expression of these transcription factors was linked to reduced expression of the enzyme FAE which is involved in the elongation of fatty acids during their biosynthesis process (Figure). Conclusions. Altered expression of nuclear receptors mediating reciprocal regulation of lipid metabolism and immune function occurs in HepG2 cells under p17 administration. These data highlight a detrimental effects of HIV proteins in resetting lipid metabolism in liver cells. These data might explain detrimental effects of HIV-HCV coinfection on lipid metabolism.

Tu2051 The HIV Matrix Protein P17 Subverts the Nuclear Receptor Transcriptome in HEPG2 Cells

Background. Matrix proteins are essential in the HIV replication cycle. The HIV matrix protein p17 serves several functions in the viral replication cycle including the viral nuclear import at early stage of infection. In the late stage, p17 mediates the recruitment of the viral surface/transmembrane gp120/gp41 envelope protein complex into virions and targets Pr55Gag proteins to their assembly sites at the plasma membrane of infected cells. Members of the nuclear receptor superfamily exert their regulatory activity integrating regulatory effects exerted by nutrients with intermediate metabolism by positively and negatively regulating the expression of effector genes. We have previously demonstrated that HIV infection is associated with an altered expression of nuclear receptor transcriptome in human monocytes as well as that stimulation of these cells with p17 down-regulates the expression of FXR and PPARγ. Aims. To analyze the effect exerted by the HIV matrix protein p17 on nuclear receptor gene expression in HepG2 cells. Methods. Serum starved HepG2 cells were stimulated 18 hours with 2 μg/ml recombinant p17 protein. At the end of the stimulation total RNA was extracted, reverse-transcribed in cDNA and amplified using specific primers for 10 nuclear receptors. Relative mRNA expression of Fatty Acid Elongase (FAE) was also investigated. Results. HepG2 cells treated with the HIV matrix protein p17 expressed an altered pattern of nuclear receptors characterized by a profound down-regulation in the expression of PPARα, -β, -γ, RARα, RXR, LXRβ, FXR, SHP, PXR and GR. Of interest, the deregulated expression of these transcription factors was linked to reduced expression of the enzyme FAE which is involved in the elongation of fatty acids during their biosynthesis process (Figure). Conclusions. Altered expression of nuclear receptors mediating reciprocal regulation of lipid metabolism and immune function occurs in HepG2 cells under p17 administration. These data highlight a detrimental effects of HIV proteins in resetting lipid metabolism in liver cells. These data might explain detrimental effects of HIV-HCV coinfection on lipid metabolism.

A Failure to Normalize Biochemical and Metabolic Insults During Morphine Withdrawal Disrupts Synaptic Repair in Mice Transgenic for HIV-gp120

Drug abuse in HIV-infected individuals accelerates the onset and progression of HIV-associated neurocognitive disorders (HAND). Opiates are a class of commonly abused drugs that have interactive effects with neurotoxic HIV proteins that facilitate glial dysfunction, neuronal damage and death. While the combined effects of neurotoxic HIV proteins and morphine have been extensively studied in the setting of chronic and acute morphine use, very little in known about the effects of HIV proteins during drug withdrawal. Since opiate withdrawal can induce considerable neuronal stress, we determined the effects of opiates (morphine) on brain redox balance, sphingolipid metabolism and synaptic integrity during both chronic and withdrawal conditions in non-transgenic mice (nTg), and in mice transgenic for the HIV-coat protein gp120 (gp120tg). In nTg mice, we found that chronic morphine increased brain oxidative capacity and induced synaptic damage that was largely reversed during drug withdrawal. Gp120tg mice showed a similar response to chronic morphine, but the diminished oxidative capacity and synaptic damage failed to normalize during drug withdrawal. In nTg mice, brain sphingolipid content was not affected by morphine during chronic or withdrawal conditions. In gp120tg mice there was a baseline perturbation in sphingolipid metabolism that manifest as decreased sphingomyelin with accumulations of the bioactive lipid ceramide. Sphingolipid metabolism was highly reactive to morphine in gp120tg mice. Chronic morphine increased sphingomyelin content with a consequent reduction in ceramide. During drug withdrawal, these effects reversed, and sphingomyelin levels were reduced with consequent increases of ceramide. We interpret these findings to suggest that neuronal repair during morphine withdrawal is inhibited in the setting of gp120 by mechanisms that involve sustained oxidative insult and accumulations of the highly reactive intermediate ceramide.

P38 MAP Kinase Inhibitor Prevents Diastolic Dysfunction in Rats Following HIV gp120 Injection In vivo

HIV infection in patients is associated with a surprisingly high frequency of diastolic dysfunction followed by the development of a dilated cardiomyopathy. Potential mechanisms include direct effects of HIV proteins, including gp120. We have previously reported direct inotropic and p38 MAP kinase signaling effects of HIV gp120 on isolated cardiac myocytes in vitro. We now report effects of a single injection of HIV gp120 on cardiac hemodynamics in vivo. HIV gp120 (50 microg/kg) was injected intravenously and hemodynamics assessed at 1, 24, 48 and 72 h in freely ambulatory, awake rats. Rats injected with gp120 demonstrated a blunted diastolic response to increasing intravenous (IV) injections of the beta-adrenergic agonist, isoproterenol (ISO), compared with similarly instrumented controls at 48 h (gp120 vs. control, P < 0.01; n = 6, for each). Pre-treatment with the p38 MAP kinase inhibitor, SB 203580, prevented the diastolic dysfunction (gp120 + SB vs. control, P = NS; n = 6, for each). Hemodynamic changes correlated with inhibition of both p38 MAP kinase and troponin I phosphorylation by SB in vivo. There were no differences in ISO dose-response curves between gp120-treated and control rats at 1, 24 or 72 h (P = NS; n = 6, for each). Thus, evidence of diastolic dysfunction is apparent in vivo in rats following a single dose of HIV gp120. To our knowledge, this is the first report of a hemodynamic effect of an HIV protein in vivo. These findings lend further support to the hypothesis that the HIV virus, itself, may contribute to myocardial dysfunction in patients infected with HIV via a p38 MAP kinase mechanism.