HIV antivirals affect endothelial activation and endothelial-platelet crosstalk.
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
Abstract
Rationale: People living with human immunodeficiency virus (PLHIV) on effective antiretroviral therapy are at increased risk of cardiovascular complications, possibly due to off-target drug effects. Some studies have associated antiretroviral therapy with increased risk of myocardial infarction and endothelial dysfunction, but a link between endothelial function and antiretrovirals has not been established. Objective: To determine the effects of antiretrovirals in common clinical use upon in vitro endothelial function in order to better understand cardiovascular risk in PLHIV. Methods and Results: Human umbilical cord vein endothelial cells (HUVEC) or human coronary artery endothelial cells (HCAEC) were pre-treated with the antiretrovirals abacavir sulphate (ABC), tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Expression of adhesion molecules, ectonucleotidases (CD39 and CD73), tissue factor (TF), endothelial-derived microparticle (EMP) numbers and phenotype, and platelet activation were evaluated by flow cytometry. TF and ectonucleotidase activities were measured using colourimetric plate-based assays. ABC-treated endothelial cells had higher levels of ICAM-1 and TF expression following TNF-α stimulation. In contrast, TDF and TAF treatment gave rise to greater populations of CD39+CD73+ cells. These cell surface differences were also observed within EMP repertoires. ABC-treated cells and EMP had greater TF activity, whilst TDF- and TAF-treated cells and EMP displayed higher ectonucleotidase activity. Finally, EMP isolated from ABC-treated cells enhanced collagen-evoked platelet integrin activation and α-granule release. Conclusions: We report differential effects of antiretrovirals used in the treatment of HIV upon endothelial function. ABC treatment led to an inflammatory, pro-thrombotic endothelial phenotype that promoted platelet activation. In contrast, TDF and TAF conferred potentially cardioprotective properties associated with ectonucleotidase activity. These observations establish a link between antiretrovirals and specific functional effects that provide insight into cardiovascular disease in PLHIV.
Date Issued
2020-11-06
Date Acceptance
2020-09-30
Citation
Circulation Research, 2020, 127 (11), pp.1365-1380
ISSN
0009-7330
Publisher
American Heart Association
Start Page
1365
End Page
1380
Journal / Book Title
Circulation Research
Volume
127
Issue
11
Copyright Statement
© 2020 American Heart Association, Inc.
Sponsor
Gilead Sciences Inc
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32998637
Grant Number
CO-UK-311-4087
Subjects
antiretroviral
cellular crosstalk
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-10-01