Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection

Ramezani, Ali; Dubrovsky, Larisa; Pushkarsky, Tatiana; Sviridov, Dmitri; Karandish, Sara; Raj, Dominic S.; Fitzgerald, Michael L.; Bukrinsky, Michael

doi:10.1124/jpet.115.224485

Cited by 15 publications

(16 citation statements)

References 53 publications

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“…7B b ), consistent with demonstrated rescue by the compound of Nef-inhibited cholesterol efflux (Fig. 7A) and previous studies demonstrating anti-HIV activity of ABCA1 and ABCA1-stimulated cholesterol efflux 28, 35, 36 . Consistent with previous studies 1, 5, 36 , cholesterol efflux from HIV-infected cells was decreased by 60%, whereas HIV-infected cells treated with NSC 13987 showed cholesterol efflux not significantly different from that of mock-infected cells (Fig.…”

Section: Resultssupporting

confidence: 91%

“…Our previous studies demonstrated that HIV critically depends on interaction with host cholesterol metabolism and modifies it for optimization of viral replication 1, 2, 28, 35, 36 . Specifically, HIV, through viral protein Nef, reduces abundance and impairs functional activity of ABCA1, a key transporter in cholesterol efflux pathway 1 .…”

Section: Discussionmentioning

confidence: 99%

“…This latter effect may have two main explanations. First, the compound prevents ABCA1 downregulation by Nef, and ABCA1 has been shown to inhibit HIV-1 replication by reducing lipid rafts abundance on the plasma membrane and affecting production and infectivity of nascent virions 3, 28, 35, 36 . Second, previous reports presented evidence that anthraquinone derivatives inhibit the ribonuclease H function of HIV-1 reverse transcriptase 43, 44 .…”

Section: Discussionmentioning

confidence: 99%

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Interaction Between HIV-1 Nef and Calnexin

Hunegnaw

Vassylyeva

Dubrovsky

et al. 2016

ATVB

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Objective HIV-infected patients are at an increased risk of developing atherosclerosis, in part due to downmodulation and functional impairment of ATP-Binding Cassette A1 (ABCA1) cholesterol transporter by the HIV-1 protein Nef. The mechanism of this effect involves Nef interacting with an endoplasmic reticulum (ER) chaperone calnexin and disrupting calnexin binding to ABCA1, leading to ABCA1 retention in ER, its degradation and resulting suppression of cholesterol efflux. However, molecular details of Nef-calnexin interaction remained unknown, limiting translational impact of this finding. Approach and results Here, we used molecular modeling and mutagenesis to characterize Nef-calnexin interaction and to identify small molecule compounds that could block it. We demonstrated that interaction between Nef and calnexin is direct and can be reconstituted using recombinant proteins in vitro with a binding affinity of 89.1 nM measured by surface plasmon resonance. The cytoplasmic tail of calnexin is essential and sufficient for interaction with Nef, and binds Nef with affinity of 9.4 nM. Replacing lysine residues in positions 4 and 7 of Nef with alanines abrogates Nef-calnexin interaction, prevents ABCA1 downregulation by Nef, and preserves cholesterol efflux from HIV-infected cells. Through virtual screening of the NCI library of compounds, we identified a compound, 1[(7-Oxo-7H-benz[de]anthracene-3-yl)amino]anthraquinone, which blocked Nef-calnexin interaction, partially restored ABCA1 activity in HIV-infected cells, and reduced foam cell formation in a culture of HIV-infected macrophages. Conclusion This study identifies potential targets that can be exploited to block the pathogenic effect of HIV infection on cholesterol metabolism and prevent atherosclerosis in HIV-infected subjects.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interaction Between HIV-1 Nef and Calnexin

Hunegnaw

Vassylyeva

Dubrovsky

et al. 2016

ATVB

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“…NDV infection disturbs the lipid metabolism in chickens [32]. Studies on various viruses demonstrate that the pharmacological agents targeting lipid metabolism can inhibit virus infection [30].…”

Section: Introductionmentioning

confidence: 99%

The LXR ligand GW3965 inhibits Newcastle disease virus infection by affecting cholesterol homeostasis

et al. 2016

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Newcastle disease (ND) is a contagious disease that affects most species of birds. Its causative pathogen, Newcastle disease virus (NDV), also exhibits considerable oncolytic activity against mammalian cancers. A better understanding of the pathogenesis of NDV will help us design efficient vaccines and novel anticancer strategies. GW3965, a widely used synthetic ligand of liver X receptor (LXR), induces the expression of LXRs and its downstream genes, including ATP-binding cassette transporter A1 (ABCA1). ABCA1 regulates cellular cholesterol homeostasis. Here, we found that GW3965 inhibited NDV infection in DF-1 cells. It also inhibited NF-κB activation and reduced the upregulation of proinflammatory cytokines induced by the infection. Further studies showed that GW3965 exerted its inhibitory effects on virus entry and replication. NDV infection increased the mRNA levels of several lipogenic genes but decreased the ABCA1 mRNA level. Overexpression of ABCA1 inhibited NDV infection and reduced the cholesterol content in DF-1 cells, but when the cholesterol was replenished, NDV infection was restored. GW3965 treatment prevented cholesterol accumulation in the perinuclear area of the infected cells. In summary, our studies suggest that GW3965 inhibits NDV infection, probably by affecting cholesterol homeostasis.

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“…For example, agonists of Liver X Receptors under development as a cardiovascular drug, were potentially active in supressing HIV and prion infection. 6,39 Infectious origin of cardiovascular diseases was once a popular hypothesis 40 and involvement of HCMV in pathogenesis of atherosclerosis was suspected for a long time. 41 Perhaps the last word on connection between infection and cardiovascular and metabolic diseases is yet to be said.…”

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confidence: 99%

Cdc42 – A tryst between host cholesterol metabolism and infection

Sviridov

Mukhamedova

2016

Small GTPases

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Emerging evidence points to an important connection between pathogenesis of intracellular infections and host cholesterol metabolism. In our study we demonstrated that human cytomegalovirus exploits host small GTPase Cdc42 to hijack cellular cholesterol efflux pathway. It appears that the virus uses host machinery to stimulate cholesterol efflux by modifying lipid rafts and altering properties of plasma membrane, but the altered pathway is controlled by the viral protein US28 instead of the host ATP binding cassette transporter A1. We speculate that viruscontrolled remodeling of plasma membrane facilitates immune evasion, exocytosis of viral proteins and cell-to-cell transmission of human cytomegalovirus. These mechanisms may be not unique for the cytomegalovirus and subverting reverse cholesterol transport pathway may be a generic mechanism used by pathogens to alter properties of host plasma membrane adapting it for their purposes-to hide and disseminate.

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Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection

Abstract: Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus

Cited by 15 publications

References 53 publications

Interaction Between HIV-1 Nef and Calnexin

Interaction Between HIV-1 Nef and Calnexin

The LXR ligand GW3965 inhibits Newcastle disease virus infection by affecting cholesterol homeostasis

Cdc42 – A tryst between host cholesterol metabolism and infection

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