Long-term treated HIV infection is associated with platelet mitochondrial dysfunction

Abstract

HIV infection and antiretroviral therapy have been linked to mitochondrial dysfunction. The role of platelet mitochondrial dysfunction in thrombosis, immunoregulation and age-related diseases is increasingly appreciated. Here, we studied platelet mitochondrial DNA content (mtDNApl) and mitochondrial function in people living with HIV (PLHIV) and related this to platelet function. In a cohort of 208 treated PLHIV and 56 uninfected controls, mtDNApl was quantified, as well as platelet activation, platelet agonist-induced reactivity and inflammation by circulating factors and flow cytometry. In a subgroup of participants, the metabolic activity of platelets was further studied by mitochondrial function tests and the Seahorse Flux Analyzer. PLHIV had significantly lower mtDNApl compared to controls (8.5 copies/platelet (IQR: 7.0–10.7) vs. 12.2 copies/platelet (IQR: 9.5–16.6); p < 0.001), also after correction for age, sex and BMI. Prior zidovudine-use (n = 46) was associated with a trend for lower mtDNApl. PLHIV also had reduced ex vivo platelet reactivity and mean platelet volume compared to controls. MtDNApl correlated positively with both platelet parameters and correlated negatively with inflammatory marker sCD163. Mitochondrial function tests in a subgroup of participants confirmed the presence of platelet mitochondrial respiration defects. Platelet mitochondrial function is disturbed in PLHIV, which may contribute to platelet dysfunction and subsequent complications. Interventions targeting the preservation of normal platelet mitochondrial function may ultimately prove beneficial for PLHIV.

Term Pregnancy Women with Human Immunodeficiency Virus Infection Receiving Antiretroviral Threapy as A Risk Factor for Low Expression of Mitochondiral Deoxyribose-Nucleic Acid in Placenta

“…The study found a significant reduction in the mean mtDNA copies/cells in the ART pregnancy group compared to the control group (p < 0.001). Comparison of mean mtDNA copies in ART-exposed pregnancies did not show significant differences in the first, second, or third trimesters [12].…”

Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy

“…infected controls [83]. The implications of mitochondrial density in PMVs is unknown; however, long-term treated HIV is associated with reduced platelet mitochondrial content, supporting the presence of MVs with lowered mitochondrial densities [88]. Circulating MVs, most of which are platelet-derived, were also implicated in adversely affecting endothelial cells in an in vitro model [87].…”

“…Characterization of circulating microvesicles through flow cytometry indicates that most of circulating MVs are PMVs (79%) in HIV infection and that these MVs have significantly lowered mitochondrial densities compared to uninfected controls [83]. The implications of mitochondrial density in PMVs is unknown; however, long-term treated HIV is associated with reduced platelet mitochondrial content, supporting the presence of MVs with lowered mitochondrial densities [88]. Circulating MVs, most of which are platelet-derived, were also implicated in adversely affecting endothelial cells in an in vitro model [87].…”

People with HIV have higher percentages of circulating CCR5+ CD8+ T cells and lower percentages of CCR5+ regulatory T cells

“…RANTES, a CCR5 ligand, was determined in PLHIV only by ELISA (R and D systems, Minneapolis, USA) in citrated plasma samples according to the manufacturer’s instructions 32 .…”