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HIV Disease Progression Is Controlled by Cell Cholesterol Homeostasis Dysregulation in Antigen Presenting Cells

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HIV Disease Progression Is Controlled by Cell Cholesterol Homeostasis Dysregulation in Antigen Presenting Cells HIV disease progression is controlled by cell cholesterol homeostasis dysregulation in antigen presenting cells Giovanna Rappocciolo, PhD Disease progression in HIV-1 controllers Poropatich and Sullivan, 2011 • <5% of HIV-1 infected individuals can control disease progression in the absence of ART. • HIV-1 nonprogressors (NP) • Include: elite controllers (EC) long term non-progressors (LTNP) and viremic controllers (VC), • Known restriction factors [HLA B*5701, CCR5-Δ32, etc] do not explain most of these. HIV-1 trans infection Trans infection Cis-infection B cells DC Macrophages HIV 10-3 m.o.i. HIV 10-3 m.o.i. HIV 10-3 m.o.i. PHA/IL2 activated CD4+T cells 50000 cis low B cells trans (low) 45000 * DC trans (low) 40000 macrophage trans (low) 35000 30000 /ml 25000 pg * * 20000 * p24 p24 15000 10000 * * * * 5000 * 0 4 8 12 Rappocciolo,G. et al. mBio, 2014 Day APC from NP do not mediate HIV-1 trans infection of CD4+ T cells DC trans infection of B cell trans infection of autologous CD4+ T cells autologous CD4+ T cells Trans infection as an intrinsic trait Vinayaka R. Prasad, and Michael I. Bukrinsky, mBio (2014) Editorial to: Rappocciolo,G. et al. mBio, 2014 Hypothesis: Altered APC cholesterol content in NP inhibits efficient HIV-1 passage through virologic synapse to CD4+ T cell CD4+ T cell CD4 T cell APC DC-SIGN CD4 HIV-1 PROGRESSOR (PR) APC CCR5/CXCR4 ICAM-1 CD4+ T cell LFA-1 Lipid raft Cholesterol HIV-1 Endosome HIV-1 NON-PROGRESSOR (NP) APC CHOLESTEROL TRAFFICKING: ENDOGENOUS AND EXOGENOUS PATHWAYS ABCG1 HDL EXOGENOUS LDL PATHWAY v Ox-LDL LDLR ABCA1 CD36 EARLY ENDOSOME v Free ABCA1 Cholesterol synthesis Low Oxysterol cholesterol cholesterol levels Statins ENDOGENOUS HMG CoA Nuclear receptor ligand (LXR,PPARɣ) reductase activationPATHWAY in APC inhibits trans infection NR PPARɣ LXR or PPARg LXR/PPRg LXR Untreated 120 SERBP 100 + TO901317 ABCA1 80 + ciglitazone 60 Transcription ABCG1 40 LDLR gene % Trans Infection Trans % 20 transcription 0 day 4 day 8 day 12 Rappocciolo,G. et al. mBio, 2014 Focused transcriptome mRNA expression levels of selective cholesterol metabolism genes in PR and NP DC 2 5 PPARγ CD36 1.5 4 3 1 2dCt - 2 0.5 PPARɣ* 1 0 0 CD36 PR NP PR NP PPARɣ* 0.06 ABCA1** ABCA1** 0.045 PPARɣ* 0.03 *3 PPARɣ isoforms. 0.015 **ABCA1 is associated with NP by 0 PCR but not by transcriptome. PR NP N=8 PR, 8 NP Rappocciolo et al. unpublished APC from NP have lower cholesterol levels compared to PR N= 5 N= 4 N=5 N= 5 N= 4 N=4 N= 4 N= 5 N=7 Rappocciolo et al. mBio 2014 Mechanisms regulating cholesterol efflux form NP APC -Cellular factors -Cholesterol acceptors -Serum factors/ bioactive metabolites? ApoA1-mediated cholesterol efflux is higher in APC from NP B cells 20 DC 15 p=0.006 p=0.002 15 10 10 p= 0.03 % Efflux % 5 5 % Efflux % 0 0 PR NP SN PR NP SN 20 CD4+ T cells 15 10 % Efflux % 5 0 PR NP SN Rappocciolo et al. unpublished Data representative of two independent experiments, in triplicate Plasma factor is related to cholesterol efflux J. Lipid Res. 2015. 56: 692–702. CHOLESTEROL TRAFFICKING: ENDOGENOUS AND EXOGENOUS PATHWAYS ABCG1 HDL EXOGENOUS LDL PATHWAY v Ox-LDL LDLR ABCA1 HDL CD36 EARLY ENDOSOME v Free ABCA1 Cholesterol synthesis Low Oxysterol cholesterol cholesterol levels Statins HMG CoA ENDOGENOUS reductase NR PPARɣ PATHWAY LXR or PPARg LXR/PPRg LXR SERBP ABCA1 Transcription ABCG1 LDLR gene transcription Apolipoprotein A2 role in HIV-1 nonprogression MACS SNP rs5082: SNP rs5082: HDL participants TT genotype CT or CC genotype NP 48 81 (N = 129) False negative True positive PPV = 81% PR 38 19 NPV = 44% (N = 57) True negative False positive • May stabilize HDL structure by its association with lipids, and affect HDL metabolism. • Defects in apolipoprotein A2 (ApoA2; ApoA-II) gene can result in ApoA2 deficiency or hypercholesterolemia. • rs5082 is a SNP in the ApoA2 gene identified by Villard et al 2013. It is affecting the transcriptional efficiency. Sera from NP induce higher cholesterol efflux than PR Efflux is higher in NP and SN than PR Efflux does not differ among the NP subgroups p<0.0001 30 30 * * x 20 20 u l f f E % % E fflux 10 10 0 0 PR NP EC VC N=29 N=32 LTNP N= 5 N=9 N= 15 *BioVision Cholesterol Efflux Assay Rappocciolo et al. unpublished Sera from NP have higher levels of APO A2 p=0.0006 15 15 10 10 m g/m l m g/m l 5 5 0 0 PR NP VC EC LTNP N = 22 N = 27 6 11 5 METABOLOMICS EPIGENETIC It is at the intersection of the genetic and environmental factors The individual metabolic fingerprint reflects alterations in homeostasis Adapted form Metabolon, Inc. Bioactive lipids 5-oxo-ETE PGE2 p= 0.02 10 p=0.05 6 ns p=0.01 8 p=0.003 p=0.009 4 6 p=0.008 4 2 2 Relative AmountRelative 0 0 AmountRelative -2 -2 PR EC LTNP VC All N P PR EC LTNP VC All N P N=14 N=5 N=8 N=9 N=22 N=14 N=5 N=8 N=9 N=22 CHOLESTEROL TRAFFICKING: ENDOGENOUS AND EXOGENOUS PATHWAYS Fatty acids Lipoxygenase HDL cycloxygenase ABCG1 EXOGENOUS LDL PATHWAY v ABCA1 Ox-LDL LDLR 5-oxo-ETE CD36 EARLY ENDOSOME v Free ABCA1 Cholesterol synthesis Low Oxysterol cholesterol cholesterol levels Statins HMG CoA ENDOGENOUS reductase NR PPARɣ PATHWAY LXR or PPARg LXR/PPRg LXR SERBP ABCA1 Transcription ABCG1 LDLR gene transcription The non-progressor puzzle: a key to curing HIV infection? Phenotype APC-mediated trans infection cholesterol homeostasis Genome Metabolomics Polymorphism in APOA2 gene Bioactive molecules CONCLUSIONS • HIV-1 NP (nonprogression) is associated with poor HIV-1 trans infection and: • Low cholesterol levels in professional APC. • Increase in cholesterol efflux and ABCA-1, ApoA1 and PPARɣ expression in APC. • Plasma factors (ApoA-2, 5-oxo-ETE, PGE2) involved in dysregulation of cell cholesterol homeostasis in NP • Is an inherited genetic trait. • Cholesterol modification therapies could have potential as adjuncts to traditional ART or to the ‘kick and kill’ approach (‘kick, starve and kill’) • HMG-CoA reductase inhibitors [statins]: atorvastatin (Lipitor), simvastatin (Zocor), and rosuvastatin (Crestor). • PCSK9 inhibitors [evolocumab (Repatha), alirocumab (Praluent)]. • We have identified individuals with a natural low-cholesterol phenotype and possible genotypes; could have implications for CVD and other diseases. • Many other viruses utilize host cholesterol during infection. ACKNOWLEDGMENTS • Diana Campbell De Lucia • Bill Buchanan and Pitt Men’s • Dr. Jeremy Martinson Study MACS staff • Dr. Paolo Piazza • MACS participants • Dr. Stacy Wendell • NIH Funding • U01-AI35041 • Kathleen Hartle • R01-AI118403 • Patrick Mehta • R37-AI41870 • Dr. Charles R. Rinaldo • T32-AI065380.
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