HIV antivirals affect endothelial activation and endothelial-platelet crosstalk

By Akif Khawaja and Mike Emerson

In a paper just accepted for publication in Circulation Research, we investigate the impact of commonly used HIV antiretroviral drugs upon in vitro endothelial activation and endothelial-platelet crosstalk.

Improvements in diagnosis and treatment have transformed HIV infection from a once fatal disease to a manageable chronic infection. Combination antiretroviral therapy (cART) has been a vital component of this transformation. cART consists of a nucleotide reverse-transcriptase inhibitor (NRTI) backbone, typically abacavir sulphate (ABC) or a tenofovir-based alternative (either tenofovir disoproxil fumarate, TDF, or tenofovir alafenamide, TAF), with a third antiretroviral agent from a different drug class. When effectively used, cART can suppress HIV replication such that patients become virologically undetectable and are no longer able to transmit HIV. Emerging evidence suggests that people living with HIV are twice as likely to develop cardiovascular complications, however the underlying mechanisms are unclear. Interestingly, some cohort studies have found a cardiovascular risk signal with ABC, suggesting that off-target drug effects may contribute to this increased relative risk. Studies have found that ABC, but not TDF or TAF, increases platelet and leukocyte activation. The effects of cART components on the endothelium are not as well characterised.

We examined the effects of ABC, TDF and TAF on endothelial functions that could contribute to the increased cardiovascular risk reported in some cohort studies. We found ABC enhanced inflammation-induced ICAM-1 and tissue factor (TF) expression in both human umbilical cord vein and coronary artery endothelial cells (HUVEC and HCAEC). These differences were also reflected in HUVEC and HCAEC endothelial-derived microparticle (EMP) repertoires, with ABC enhancing the number of EMP carrying ICAM-1 and TF. In contrast, HUVEC and HCAEC treated with TDF or TAF had higher ectonucleotidase levels (CD39 and CD73) and produced more ectonucleotidase carrying EMP.

Since, ectonucleotidases hydrolyse ATP, which is associated with platelet and leukocyte activation, TDF and TAF may be relatively cardioprotective. Interestingly, these differences in expression had functional implications, with both ABC-treated cells and EMP having higher TF activity and TDF/TAF-treated cells and EMP having higher ectonucleotidase activity. EMP isolated from ABC-treated cells were also able to enhance platelet activation compared to vehicle-, TDF- and TAF-treated controls, suggesting that ABC also alters endothelial-platelet crosstalk. This work links a specific and avoidable antiretroviral drug with endothelial activation and demonstrates that in vitro endothelial studies can be used to probe the cardiovascular risk profiles of clinically used antiretrovirals. Our work could potentially aid a more personalised approach to managing HIV infection and so as to reduce cardiovascular co-morbidity.

Link to publication: https://pubmed.ncbi.nlm.nih.gov/32998637/

References

Khawaja AA, Taylor KA, Lovell AO, Nelson M, Gazzard B, Boffito M and Emerson M. HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk. Circ Res. 2020.