Abstract
BackgroundApolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain. Three isoforms of ApoE (ApoE2, ApoE3, ApoE4) exist in humans, and their relative expression levels impact HIV-1 infection, HIV-1/AIDS disease progression, and cognitive decline associated with HIV-1-associated neurocognitive disorder. Because HIV-1 Tat, a viral protein essential for HIV-1 replication, can bind to low-density lipoprotein receptor-related protein 1 (LRP1) that controls ApoE uptake in the brain, we determined the extent to which different isoforms of ApoE affected Tat-mediated HIV-1 LTR transactivation.MethodsUsing U87MG glioblastoma cells expressing LTR-driven luciferase, we determined the extent to which LRP1 as well as ApoE2, ApoE3, and ApoE4 affected Tat-mediated HIV-1 LTR transactivation.ResultsA specific LRP1 antagonist and siRNA knockdown of LRP1 both restricted significantly Tat-mediated LTR transactivation. Of the three ApoEs, ApoE4 was the least potent and effective at preventing HIV-1 Tat internalization and at decreasing Tat-mediated HIV-1 LTR transactivation. Further, Tat-mediated LTR transactivation was attenuated by an ApoE mimetic peptide, and ApoE4-induced restriction of Tat-mediated LTR transactivation was potentiated by an ApoE4 structure modulator that changes ApoE4 into an ApoE3-like phenotype.ConclusionsThese findings help explain observed differential effects of ApoEs on HIV-1 infectivity and the prevalence of HAND in people living with HIV-1 infection and suggest that ApoE mimetic peptides and ApoE4 structure modulator might be used as a therapeutic strategy against HIV-1 infection and associated neurocognitive disorders.
Highlights
Apolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain
We found that lipoprotein receptor-related protein 1 (LRP1) was involved in transcription protein (Tat)-mediated HIV-1 long terminal repeat (LTR) transactivation, that ApoE4 was less effective than ApoE2 and ApoE3 in preventing HIV-1 Tat internalization and Tat-mediated HIV-1 LTR transactivation, that an ApoE mimetic peptide attenuated Tat-mediated LTR transactivation, and that an ApoE4 structure modulator enhanced the effectiveness of ApoE4 in blocking Tat-mediated HIV-1 LTR transactivation
Concentration-dependent increases in Tat-mediated HIV-1 LTR transactivation were observed when exogenous HIV-1 Tat protein was co-applied at an optimal concentration of 100 μM chloroquine (Additional file 1: Figure S1), a weak base that neutralizes the acidic environment of lysosomes, prevents HIV-1 Tat degradation, and enhances nuclear delivery of HIV-1 Tat [26, 31,32,33]
Summary
Apolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain. Three isoforms of ApoE (ApoE2, ApoE3, ApoE4) exist in humans, and their relative expression levels impact HIV-1 infection, HIV-1/AIDS disease progression, and cognitive decline associated with HIV-1-associated neurocognitive disorder. Because HIV-1 Tat, a viral protein essential for HIV-1 replication, can bind to low-density lipoprotein receptor-related protein 1 (LRP1) that controls ApoE uptake in the brain, we determined the extent to which different isoforms of ApoE affected Tat-mediated HIV-1 LTR transactivation. Apolipoprotein E (ApoE), an apolipoprotein that mediates the transport and delivery of cholesterol and lipids through cell surface ApoE receptors [1], is highly expressed in the brain, and it plays a critical role in maintaining brain function [2, 3]. Additional strategies are needed to block viral reactivation to maintain HIV-1 in a state of
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