HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk

Circ Res. 2020 Nov 6;127(11):1365-1380. doi: 10.1161/CIRCRESAHA.119.316477. Epub 2020 Oct 1.

Abstract

Rationale: People living with HIV 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 to better understand cardiovascular risk in people living with HIV.

Methods and results: Human umbilical cord vein endothelial cells or human coronary artery endothelial cells were pretreated with the antiretrovirals abacavir sulphate (ABC), tenofovir disoproxil fumarate, or tenofovir alafenamide. 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 (intercellular adhesion molecule)-1 and TF expression following TNF (tumor necrosis factor)-α stimulation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide 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, while tenofovir disoproxil fumarate- and tenofovir alafenamide-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, prothrombotic endothelial phenotype that promoted platelet activation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide 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 people living with HIV.

Keywords: abacavir; cardiovascular disease; endothelial cells; flow cytometry; tenofovir.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / metabolism
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Alanine
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Apyrase / metabolism
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cell Adhesion Molecules / metabolism
  • Cell Communication / drug effects*
  • Cell-Derived Microparticles / drug effects*
  • Cell-Derived Microparticles / metabolism
  • Cells, Cultured
  • Dideoxynucleosides / pharmacology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • GPI-Linked Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Platelet Activation / drug effects*
  • Signal Transduction
  • Tenofovir / pharmacology
  • Thromboplastin / metabolism

Substances

  • Anti-HIV Agents
  • Cell Adhesion Molecules
  • Dideoxynucleosides
  • GPI-Linked Proteins
  • Thromboplastin
  • Tenofovir
  • 5'-Nucleotidase
  • NT5E protein, human
  • Apyrase
  • ENTPD1 protein, human
  • tenofovir alafenamide
  • Adenine
  • Alanine
  • abacavir