Ageing HIV-infected patients present an increased incidence of cardiovascular diseases, endothelial dysfunction being an early alteration. Some protease inhibitors (PIs) have been shown to increase the risk of cardiovascular disease. We evaluated here the effects of CCR5 or integrase inhibitors as compared to PIs on endothelial functions in vitro.
Methods
Human coronary artery endothelial cells (HCAEC) from adult and old non-HIV-infected donors were treated for 15 days with the CCR5 inhibitor mara-viroc, the integrase inhibitors dolutegravir or raltegravir or the ritonavir-boosted PIs, darunavir (DRV/r) or atazanavir (ATV/r), all at Cmax concentrations. We evaluated endothelial function, secretion of adhesion molecules and cytokines, inflammation, oxidative stress and senescence.
Results
In endothelial cells from adult donors, we con-firmed that ATV/r and DRV/r adversely affected all assessed endothelial functions and enhanced senescence, these effects being mild for DRV/r. Raltegravir had no effect and maraviroc a mild anti-inflammatory effect. Dolutegravir decreased inflammation, by inhibiting the NFκB pathway, and senescence, by repressing the p21 pathway. Moreover, HCAEC from an old donor presented, constitutively, a high level of senescence. Raltegravir mildly affected inflammation and senescence while maraviroc and dolutegravir decreased oxidative stress, inflammation and senescence and improved endothelial dysfunction.
Conclusions
We report here that the integrase inhibitor dolutegravir and the CCR5 inhibitor maraviroc reduced inflammation of human adult endothelial cells to different extents while raltegravir was neutral. Dolutegravir also reduced senescence, while PI/r increased inflammation and senescence. It is important to address the clinical relevance of these results.
References
1.
BoccaraF., LangS., MeulemanC.HIV and coronary heart disease: time for a better understanding.J Am Coll Cardiol2013; 61: 511–523.
2.
NouE., LoJ., HadiganC., GrinspoonS.K.Pathophysiology and management of cardiovascular disease in patients with HIV.Lancet Diabetes Endocrinol2016; 4: 598–610.
3.
GuaraldiG., ZonaS., OrlandoG.Human immunodeficiency virus infection is associated with accelerated atherosclerosis.J Antimicrob Chemother2011; 66: 1857–1860.
4.
SchoutenJ., WitF.W., StolteI.G.Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study.Clin Infect Dis2014; 59: 1787–1797.
5.
DAD Study Group, Friis-Moller N, Reiss P, et al.Class of antiretroviral drugs and the risk of myocardial infarction.N Engl J Med2007; 356: 1723–1735.
6.
LangS., Mary-KrauseM., CotteL.Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4.Arch Intern Med2010; 170: 1228–1238.
7.
SteinJ.H., RibaudoH.J., HodisH.N.A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness.AIDS2015; 29: 1775–1783.
8.
GuptaS.K., MiD., MoeS.M., DubeM.P., LiuZ.Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial.J Acquir Immune Defic Syndr2013; 64: 279–283.
9.
HatanoH., ScherzerR., WuY.A randomized controlled trial assessing the effects of raltegravir intensification on endothelial function in treated HIV infection.J Acquir Immune Defic Syndr2012; 61: 317–325.
10.
LakeJ.C., KoteffJ., BrennanC.Cardiovascular biomarkers after switching to ABC/DTG/3TC: The STRIIVING Study.23rd Conference on Retroviruses and Opportunistic Infections. 22–25 February 2016, Boston, MA, USA. Abstract 660.
11.
RojasJ., BlancoJ.L., MarcosM.A.Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression.J Antimicrob Chemother2016; 71: 1975–1981.
12.
HilemanC.O., KinleyB., Scharen-GuivelV.Differential reduction in monocyte activation and vascular inflammation with integrase inhibitor-based initial antiretroviral therapy among HIV-infected individuals.J Infect Dis2015; 212: 345–354.
13.
MaguireJ.J., JonesK.L., KucR.E., ClarkeM.C., BennettM.R., DavenportA.P.The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro.Cardiovasc Res2014; 101: 513–521.
14.
CiprianiS., FrancisciD., MencarelliA.Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice.Circulation2013; 127: 2114–2124.
DonatoA.J., MorganR.G., WalkerA.E., LesniewskiL.A.Cellular and molecular biology of aging endothelial cells.J Mol Cell Cardiol2015; 89: 122–135.
17.
DonatoA.J., PierceG.L., LesniewskiL.A., SealsD.R.Role of NFkappaB in age-related vascular endothelial dysfunction in humans.Aging (Albany NY)2009; 1: 678–680.
18.
DonatoA.J., BlackA.D., JablonskiK.L., GanoL.B., SealsD.R.Aging is associated with greater nuclear NF kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans.Aging Cell2008; 7: 805–812.
19.
KrikkeM., TesselaarK., ArendsJ.E.Maraviroc intensification improves endothelial function in abacavir-treated patients, an open-label randomized cross-over pilot study.Infect Dis Ther2016; 5: 389–404.
20.
van DeursenJ.M.The role of senescent cells in ageing.Nature2014; 509: 439–446.
21.
LagathuC.C., CossarizzaA., BereziatV., NasiM., CapeauJ., PintiM.Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers.AIDS2017; 31Suppl 2: S105–S119.
22.
YinH., PickeringJ.G.Cellular senescence and vascular disease: novel routes to better understanding and therapy.Can J Cardiol2016; 32: 612–623.
23.
AuclairM., AfonsoP., CapelE., Caron-DebarleM., CapeauJ.Impact of darunavir, atazanavir and lopinavir boosted with ritonavir on cultured human endothelial cells: beneficial effect of pravastatin.Antivir Ther2014; 19: 773–782.
24.
LefevreC., AuclairM., BoccaraF.Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin.Arterioscler Thromb Vasc Biol2010; 30: 2611–2620.
CoffinierC., HudonS.E., FarberE.A.HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells.Proc Natl Acad Sci U S A2007; 104: 13432–13437.
27.
CoffinierC., HudonS.E., LeeR.A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells.J Biol Chem2008; 283: 9797–9804.
28.
MonforteA., ReissP., RyomL.Atazanavir is not associated with an increased risk of cardio- or cerebrovascular disease events.AIDS2013; 27: 407–415.
29.
DekkerD., DorresteijnM.J., PijnenburgM.The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus.Arterioscler Thromb Vasc Biol2011; 31: 458–463.
TorrianiF.J., KomarowL., ParkerR.A.Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s.J Am Coll Cardiol2008; 52: 569–576.
32.
BernalE., VerduJ.M., VeraF.Improvement of endothelial function after switching previously treated HIV-infected patients to an NRTI-sparing bitherapy with maraviroc.J Int AIDS Soc2014; 17: 19726.
33.
Diaz-DelfinJ., DomingoP., GiraltM., VillarroyaF.Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation.Cytokine2013; 61: 808–815.
34.
ZhangX., CaoR., LiuR.Reduction of the HIV protease inhibitor-induced ER stress and inflammatory response by raltegravir in macrophages.PLoS One2014; 9: e90856.
35.
MartinezE., D'AlbuquerqueP.M., LlibreJ.M.Changes in cardiovascular biomarkers in HIV-infected patients switching from ritonavir-boosted protease inhibitors to raltegravir.AIDS2012; 26: 2315–2326.
36.
SilvaE.F., CharreauI., GourmelB.Decreases in inflammatory and coagulation biomarkers levels in HIV-infected patients switching from enfuvirtide to raltegravir: ANRS 138 substudy.J Infect Dis2013; 208: 892–897.
37.
BernardinoJ.I., MocroftA., MallonP.W.Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.Lancet HIV2015; 2: e464–e473.
38.
DonatoA.J., MagerkoK.A., LawsonB.R., DurrantJ.R., LesniewskiL.A., SealsD.R.SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.J Physiol2011; 589: 4545–4554.
39.
WinnikS., AuwerxJ., SinclairD.A., MatterC.M.Protective effects of sirtuins in cardiovascular diseases: from bench to bedside.Eur Heart J2015; 36: 3404–3412.
40.
GorenneI., KumarS., GrayK.Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis.Circulation2013; 127: 386–396.
41.
Bonello-PalotN., SimonciniS., RobertS.Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment.Atherosclerosis2014; 237: 45–52.
42.
BidaultG., GarciaM., VantyghemM.C.Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction.Arterioscler Thromb Vasc Biol2013; 33: 2162–2171.
43.
AfonsoP., AuclairM., BoccaraF.LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: role of ZMPSTE24 downregulation.Atherosclerosis2016; 245: 200–211.
44.
RagnauthC.D., WarrenD.T., LiuY.Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.Circulation2010; 121: 2200–2210.
45.
BastardJ.P., FellahiS., CouffignalC.Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity.J Antimicrob Chemother2015; 70: 1816–1824.
46.
NeuhausJ., JacobsD.R.Jr., BakerJ.V.Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection.J Infect Dis2010; 201: 1788–1795.
