HIV‐Associated Lipodystrophy Syndrome

Qaqish, Roula B.; Fisher, Evelyn; Rublein, John; Wohl, David A.

doi:10.1592/phco.20.1.13.34667

Cited by 48 publications

(34 citation statements)

References 29 publications

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“…The cause of this syndrome is not clear but seems to be multifactorial. The HIV-1 infection itself seems to contribute to the development of these pathologic changes or increases the vulnerability of patients to develop the syndrome upon uptake of anti-HIV-1 drugs; some AIDS patients develop the characteristic features and metabolic disturbances of the syndrome before treatment (26,51,52). Our results suggest that Vpr might contribute to the insulin resistance of AIDS patients through both its FOXO-related insulin action blockade and its previously described glucocorticoid receptor coactivator activity (12,13).…”

Section: Discussionmentioning

confidence: 63%

HIV-1 Accessory Protein Vpr Inhibits the Effect of Insulin on the Foxo Subfamily of Forkhead Transcription Factors by Interfering With Their Binding to 14-3-3 Proteins

et al. 2005

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HIV-1 accessory protein Vpr arrests host cells at the G2/M phase of the cell cycle by interacting with members of the protein family 14-3-3, which regulate the activities of "partner" molecules by binding to their phosphorylated serine or threonine residues and changing their intracellular localization and/or stability. Vpr does this by facilitating the association of 14-3-3 to its partner protein Cdc25C, independent of the latter's phosphorylation status. Here we report that the same viral protein interfered with and altered the activity of another 14-3-3 partner molecule, Foxo3a, a subtype of the forkhead transcription factors, by inhibiting its association with 14-3-3. Foxo3a's transcriptional activity is normally suppressed by insulin-induced translocation of this protein from the nucleus into the cytoplasm. Vpr inhibited the ability of insulin or its downstream protein kinase Akt to change the intracellular localization of Foxo3a preferentially to the cytoplasm. This HIV-1 protein also interfered with insulin-induced coprecipitation of 14-3-3 and Foxo3a in vivo and antagonized the negative effect of insulin on Foxo3a-induced transactivation of a FOXO-responsive promoter. Moreover, Vpr antagonized insulin-induced suppression of the mRNA expression of the glucose 6-phosphatase, manganese superoxide dismutase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in HepG2 cells. These findings indicate that Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. Vpr thus may contribute to the tissue-selective insulin resistance often observed in HIV-1-infected individuals.

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Section: Discussionmentioning

confidence: 63%

HIV-1 Accessory Protein Vpr Inhibits the Effect of Insulin on the Foxo Subfamily of Forkhead Transcription Factors by Interfering With Their Binding to 14-3-3 Proteins

et al. 2005

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“…It has recently been reported that long-term HAART is associated with metabolic side-effects, such as lipodystrophy (Carr et al, 1998;Qaqish et al, 2000). Development of lipodystrophy is linked to the use of protease inhibitors, though it was also reported in patients receiving only RT inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Three-Drug Combinations of Emivirine and Nucleoside Reverse Transcriptase Inhibitors in Vitro: Long-Term Culture of HIV-1-Infected Cells and Breakthrough Viruses

Nitanda

Wang

Somekawa

et al. 2001

Antivir Chem Chemother

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Emivirine (EMV) is a non-nucleoside reverse transcriptase inhibitor currently undergoing Phase IIIclinical trials in HIV-1-infected patients. In this study, the anti-HIV-1 activity of EMV in combination with two nucleoside reverse transcriptase inhibitors was examined in cell cultures. The combinations EMV plus stavudine (d4T) plus lamivudine (3TC) and EMV plus d4T plus didanosine (ddI) synergistically inhibited HIV-1 replication in MT-4 cells. Although not statistically significant, EMV plus d4T plus 3TC appeared to be more synergistic than EMV plus d4T plus ddI. Synergism was also observed with any two-drug combinations, such as EMV plus d4T, EMV plus 3TC, EMV plus ddI, d4T plus 3TC, or d4T plus ddI. The three-drug combinations completely suppressed HIV-1 replication for at least 40 days after virus infection. Except for d4T, virus emerged in the presence of every compound alone or some combinations at lower concentrations. Susceptibility tests of the breakthrough viruses to each compound showed that the viruses obtained in the presence of EMV alone and 3TC alone were significantly less susceptible to EMV and 3TC, respectively. These viruses had specific amino acid mutations in their reverse transcriptase.

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“…1 HAART has been associated with numerous affects on lipid metabolism, including subcutaneous fat wasting, abdominal obesity, insulin resistance, and hyperlipidemia. 2,3 Metabolic complications arising from HAART may be due to drug-drug interactions, exacerbation of preexisting conditions, reconstitution of immune system function, or a combination. 2,3 Studies of hyperlipidemia in HIV-infected persons are complicated because dyslipidemia may occur in the absence of therapy (reviewed in Safrin and Grunfeld 3 ).…”

mentioning

confidence: 99%

“…2,3 Studies of hyperlipidemia in HIV-infected persons are complicated because dyslipidemia may occur in the absence of therapy (reviewed in Safrin and Grunfeld 3 ). Although HIV infection itself and treatment with reverse transcriptase inhibitors have been associated with altered metabolism, [2][3][4][5][6] substantial evidence indicates a role for some PIs in causing metabolic complications.…”

mentioning

confidence: 99%

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

Lenhard

Croom

Weiel

et al. 2000

ATVB

134

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Abstract-Hyperlipidemia may complicate the use of HIV protease inhibitors (PIs) in AIDS therapy. To determine the cause of hyperlipidemia, the effect of PIs on lipid metabolism was examined with HepG2 liver cells and AKR/J mice. In HepG2 cells, the PIs ABT-378, nelfinavir, ritonavir, and saquinavir stimulated triglyceride synthesis; ritonavir increased cholesterol synthesis; and amprenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA expression of diacylglycerol acyltransferase and fatty acid synthase. The retinoid X receptor agonist LG100268, but not the antagonist LG100754, further increased PI-stimulated triglyceride synthesis and mRNA expression of fatty acid synthase in vitro. In fed mice, nelfinavir or ritonavir did not affect serum glucose and cholesterol, whereas triglyceride and fatty acids increased 57% to 108%. In fasted mice, ritonavir increased serum glucose by 29%, cholesterol by 40%, and triglyceride by 99%, whereas nelfinavir had no effect, suggesting these PIs have different effects on metabolism. Consistent with the in vitro results, nelfinavir and ritonavir increased triglyceride 2-to 3-fold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. We propose that PI-associated hyperlipidemia is due to increased hepatic triglyceride synthesis and suggest that retinoids or meal restriction influences the effects of select PIs on lipid metabolism. HAART has been associated with numerous affects on lipid metabolism, including subcutaneous fat wasting, abdominal obesity, insulin resistance, and hyperlipidemia. 2,3 Metabolic complications arising from HAART may be due to drug-drug interactions, exacerbation of preexisting conditions, reconstitution of immune system function, or a combination. 2,3 Studies of hyperlipidemia in HIV-infected persons are complicated because dyslipidemia may occur in the absence of therapy (reviewed in Safrin and Grunfeld 3 ). Although HIV infection itself and treatment with reverse transcriptase inhibitors have been associated with altered metabolism, 2-6 substantial evidence indicates a role for some PIs in causing metabolic complications.PIs are important therapeutically because they inhibit virus release from infected cells, reducing virus proliferation and subsequent infection. 7 The currently available PIs include amprenavir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and ABT-378 (lopinavir; delivered in combination with RTV to enhance systemic exposure to ABT-378). The antiviral activity among individual PIs is variable and correlates with the ability to inhibit the HIV protease (ie, IC 50 0.10 to 20 nmol/L). Although these drugs contain a synthetic analog of the phenylalanine-proline amino acid sequence cleaved by the HIV protease, structural differences result in unique resistance and metabolic effects for each PI. 7 Initial reports in 1997 indicated that a number of patients developed hyperlipidemia after PI therapy. Several studies specifically implicated RTV, RTV/SQV, or NFV thera...

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HIV‐Associated Lipodystrophy Syndrome

Cited by 48 publications

References 29 publications

HIV-1 Accessory Protein Vpr Inhibits the Effect of Insulin on the Foxo Subfamily of Forkhead Transcription Factors by Interfering With Their Binding to 14-3-3 Proteins

HIV-1 Accessory Protein Vpr Inhibits the Effect of Insulin on the Foxo Subfamily of Forkhead Transcription Factors by Interfering With Their Binding to 14-3-3 Proteins

Three-Drug Combinations of Emivirine and Nucleoside Reverse Transcriptase Inhibitors in Vitro: Long-Term Culture of HIV-1-Infected Cells and Breakthrough Viruses

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

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