Stimulation of the Liver X Receptor Pathway Inhibits HIV-1 Replication via Induction of ATP-Binding Cassette Transporter A1

Morrow, Matthew P.; Grant, Angela; Mujawar, Zahedi; Dubrovsky, Larisa; Pushkarsky, Tatiana; Kiselyeva, Yana; Jennelle, Lucas T.; Mukhamedova, Nigora; Remaley, Alan T.; Kashanchi, Fatah; Sviridov, Dmitri; Bukrinsky, Michael

doi:10.1124/mol.110.065029

Cited by 54 publications

(65 citation statements)

References 41 publications

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“…Our fi nding that infectivity of HIV-1 virions produced by lymphocytes is much higher than infectivity of virions released by MDM and that this difference is eliminated when ABCA1 expression in MDM is knocked down by siRNA is consistent with our previous report that ABCA1 inhibits HIV-1 infectivity via decreasing cholesterol in lipid rafts and thus limiting cholesterol incorporated into nascent HIV virions ( 6 ). However, this is the fi rst demonstration that such activity may have implications for HIV-1 replication in natural target cells.…”

Section: Hiv-1 Infectivity Negatively Correlates With Abca1 Expressiosupporting

confidence: 92%

“…Lipid rafts are the preferential sites of HIV-1 assembly and budding, and cholesterol content of lipid rafts determines the cholesterol content of virions, which is critical for virion infectivity. Cholesterol depletion of HIV-infected cells reduces infectivity of released virions, which was shown to correlate with the amount of virion-associated cholesterol and the activity of Nef ( 6,13 ). In addition, depletion of cellular cholesterol, which reduces the abundance of rafts, also reduces HIV-1 particle production ( 6,10 ).…”

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

“…Furthermore, extracellular Nef secreted by HIV-infected cells can inhibit cholesterol efflux from uninfected cells and cause impairment of systemic reverse cholesterol transport ( 5 ). On the other hand, stimulation of cholesterol effl ux through activation of ABCA1 suppresses HIV-1 infection ( 6 ). These fi ndings suggest that interaction between Nef and ABCA1 may be a key to both viral replication and impairment of cellular lipid metabolism.…”

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

“…Cholesterol depletion of HIV-infected cells reduces infectivity of released virions, which was shown to correlate with the amount of virion-associated cholesterol and the activity of Nef ( 6,13 ). In addition, depletion of cellular cholesterol, which reduces the abundance of rafts, also reduces HIV-1 particle production ( 6,10 ). Therefore, primary cholesterol-related activity of Nef may be to increase the abundance of lipid rafts, thus stimulating production and infectivity of nascent HIV virions.…”

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

“…We previously demonstrated that pharmacological stimulation of ABCA1 expression inhibits HIV-1 infectivity by depleting viral cholesterol ( 6 ). An intriguing consequence effects on macrophage immune functions ( 31 ).…”

Section: Hiv-1 Infectivity Negatively Correlates With Abca1 Expressiomentioning

confidence: 99%

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HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Cui

Grant

Mukhamedova

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words cholesterol metabolism • cholesterol traffi cking • ATP binding cassette transporter A1 • human immunodeficiency virus Impairment of cholesterol metabolism plays a key role in pathogenesis of many disorders, most importantly cardiovascular and neurodegenerative diseases. Many infectious agents, from prions to parasites, affect cholesterol metabolism of the host. Microorganisms modify host cholesterol metabolism for two main reasons: to satisfy their own requirements for cholesterol at different stages of their life cycle, and to weaken the immune response of the host. These modifi cations may cause "unintended" consequences, triggering development of diseases that are not directly related to infection. This situation is exemplifi ed by the increased risk of atherosclerosis coincident with HIV infection. Targeting cholesterol metabolism for antimicrobial intervention, while at the same time correcting metabolic consequences of the infection, is a tempting possibility limited by the lack of knowledge about mechanisms of interaction between microorganisms and pathways of cholesterol metabolism in host cells.

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Section: Hiv-1 Infectivity Negatively Correlates With Abca1 Expressiosupporting

confidence: 92%

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

Section: Lipid Raft Cholesterol Content Analysismentioning

confidence: 99%

Section: Hiv-1 Infectivity Negatively Correlates With Abca1 Expressiomentioning

confidence: 99%

See 3 more Smart Citations

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Cui

Grant

Mukhamedova

et al. 2012

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

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Liver X receptors link lipid metabolism and inflammation

2017

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The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit pro-inflammatory gene expression. This Review will highlight recent studies that connect LXR-dependent control of lipid metabolism to regulation of the immune response.

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Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes

Zeng

et al. 2020

Hepatology

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Background and Aims Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. Approach and Results In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV‐infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR‐623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long‐lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti‐HBV effect was observed in HepG2‐derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α‐hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. Conclusions We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti‐HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.

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Stimulation of the Liver X Receptor Pathway Inhibits HIV-1 Replication via Induction of ATP-Binding Cassette Transporter A1

Cited by 54 publications

References 41 publications

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Liver X receptors link lipid metabolism and inflammation

Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes

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