Kelesidis T, Kendall MA, Yang OO, Currier JS for the NWCS 332/A5078 Team
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Transcript of Kelesidis T, Kendall MA, Yang OO, Currier JS for the NWCS 332/A5078 Team
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The Interplay of the Osteoprotegerin/RANKL Axis and Dysfunctional HDL in HIV-Infected Adults AIDS Clinical Trials Group Study NWCS 332/A5078
Kelesidis T, Kendall MA, Yang OO, Currier JS for the NWCS 332/A5078 Team
Abstract THAB0201, IAS 2012, July 26th, 2012
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Oxidized Lipids as a link between oxidative stress and the RANKL-OPG pathway
Oxidative stress
Abstract THAB0201, IAS 2012, July 26th, 2012Graham et al Clin Immunol 2009; Graham et al J Bone Miner Res 2010; Zhang et al Diabetes Metab Res Rev 2010; 26(6):455-463).
RANKL
OPG
T cells
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CD4 T cells CD8 T cells
TRAILOPG
RANKL
T cell activationB cells
HIV infection
INFLAMMATION: Proinflammatory cytokines and chemokines
ARTHIV infection
HIV infection as a model for systemic oxidative stress: Possible cross-talk between HIV infection and the RANKL-OPG axis
• Antivir Ther 2011; 16:1063; AIDS 2005; 19:1240; AIDS 2007; 21:1129; J Med Virol 2007; 79:1446-1454Abstract THAB0201, IAS 2012, July 26th, 2012
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Dysfunctional HDL in the intersection of HIV infection and the RANKL-OPG axis
• We have previously shown that HIV-infected subjects with suppressed viremia have dysfunctional HDL and that oxidized HDL is dysfunctional HDL Kelesidis et al JLR 2011, Lipids Health Dis 2011, Lipids Health Dis 2012
• Limited data exist regarding the relationship between dysfunctional HDL (ox-HDL) and the osteoprotegerin (OPG)/receptor activator of the NF-kB ligand (RANKL) in HIV infection.
Abstract THAB0201, IAS 2012, July 26th, 2012
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Hypothesis/Study Aims
We hypothesized that increased serum levels of RANKL/OPG are independently associated with lipid levels and functional (redox) properties of HDL in HIV infected subjects
RANKL
OPG
RANKL/OPG
Lipid levels (TC, HDL, LDL)
HDL redox activity (HDLox)
Abstract THAB0201, IAS 2012, July 26th, 2012
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Kelesidis et al J Lipid Res 2011 52(12):2341-51Abstract THAB0201, IAS 2012, July 26th, 2012
Methods: Oxidation rate of a fluorescent probe (DOR) as an vitro biochemical measure of HDL redox activity
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HIV-uninfected subjects (n=36)
Non-PI n=26 (47%)
Design: We used a subgroup of stored serum samples (n=91) from a previously completed prospective matched 3-year study (ACTG 5078) (Currier J et al AIDS 2007, 21:1137-1145)
HIV-infected (HIV RNA < 500 copies/mL (n=55)
PI n=29 (53%)
Abstract THAB0201, IAS 2012, July 26th, 2012
Matched by: • Cardiovascular
risk factors • Age within 5 years• Race• Sex• Blood pressure
status• Smoking status• Menopausal
status
Design
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Results (1) : Metabolic Abnormalities HIV vs Control
Characteristic Total
(N=91)HIV
(N=55)Not HIV (N=36)
P value
Gender Male 84 (92%) 52 (95%) 32 (89%) 0.428Age (years) Median
(IQR)41 (36-45) 41 (37-45) 40 (36-45) 0.589
Race/Ethnicity White Non-Hispanic
69 (76%) 42 (76%) 27 (75%) 0.547
Hispanic 17 (19%) 9 (16%) 8 (22%) Metabolic Syndrome
Present 11 (12%) 10 (18%) 1 (3%) 0.045
Triglycerides (mg/dl)
≥ 150 39 (43%) 29 (53%) 10 (28%) 0.030
Use of Lipid Lowering
Drugs
Any 12 (13%) 12 (22%) 0 (0%) 0.003
Abstract THAB0201, IAS 2012, July 26th, 2012
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Results (2): HIV infected subjects had significantly lower RANKL and RANK/OPG compared to uninfected subjects
Abstract THAB0201, IAS 2012, July 26th, 2012
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Results (3) Baseline levels of the rate of oxidation of the fluorescent probe did not significantly differ between HIV infected and uninfected subjects
Abstract THAB0201, IAS 2012, July 26th, 2012
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Results (4) Serum levels of RANKL-OPG axis are independently associated with baseline levels of lipids and Dysfunctional HDL in HIV-
1 infection
For each 10 units > average baseline RANKL/OPG
DOR by 0.81 (0.16, 1.47) x 104 FU/min
In multivariate analyses within the HIV-infected (but NOT within uninfected)subjects
HDL redox activity
↑ HDL ≥35 mg/dl ΔRANKL
ΔOPG↑ Τotal cholesterol ≥ 200 mg/dl
Abstract THAB0201, IAS 2012, July 26th, 2012
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Results (5) The RANKL/OPG NFkB pathway is associated with changes in levels of lipids in HIV-infected subjects
Abstract THAB0201, IAS 2012, July 26th, 2012
HIV Non HIV
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HD
L re
dox
activ
ity (F
U/m
in)
RANKL/OPG ratio RANKL (pg/ml)
HIV
HD
L re
dox
activ
ity (F
U/m
in)
RANKL (pg/ml)
RANKL/OPG ratio
Non HIV
Results (6) The RANKL/OPG NFkB pathway is associated with HDL redox activity in HIV-infected subjects
Abstract THAB0201, IAS 2012, July 26th, 2012
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Summary
• HIV-infected subjects on ART had significantly lower levels of total serum RANKL and RANKL/OPG ratio compared to HIV-uninfected subjects at both baseline and after 2-3 years of follow-up.
• Higher baseline levels of HDL and total cholesterol were significantly associated with higher ΔRANKL and ΔOPG in HIV infected but not in uninfected subjects.
• Functional properties of HDL were significantly associated with the serum RANKL/OPG ratio in HIV infected but not in uninfected subjects.
Abstract THAB0201, IAS 2012, July 26th, 2012
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Conclusions
• RANKL/OPG axis may be aberrantly regulated in HIV-infected compared to -uninfected adults and is independently associated with baseline levels of cholesterol and changes in functional properties of HDL in HIV-infected subjects.
• The interplay between T lymphocytes, lipids may explain our findings.
• These in vivo data are consistent with previous in vitro results that have shown that oxidized HDL may affect the NF-kB pathway (Clin Immunol 2009; 133(2):265-275; J Bone Miner Res 2010; 25(11):2460-2469; Diabetes Metab Res Rev 2010; 26(6):455-463).
• Further studies need to establish the relationship between lipids, T cells, RANKL-OPG axis and HDL function in HIV infection.
Abstract THAB0201, IAS 2012, July 26th, 2012
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AcknowledgementsStatistician: Michelle Kendall, M.S., HSPHInvestigators: Judith Currier, M.D., M.Sc., UCLA Otto Yang, MD, UCLA
Howard Hodis, MD USC Special Thanks to the Study Participants