Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus‐associated cardiovascular risk

Taylor, Kirk A.; Smyth, Erica; Rauzi, Francesca; Cerrone, Maddalena; Khawaja, Akif A.; Gazzard, Brian; Nelson, Mark; Boffito, Marta; Emerson, Michael

doi:10.1111/bph.14589

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…Even though these NRTIs are known to have lower mitochondrial toxicity 1 , it is unclear whether long-term treatment does not exert any cumulative reduction in mtDNA pl too. While ABC-use has been linked to platelet perturbations in multiple studies [43][44][45] , others could not confirm ABC associated platelet dysfunction 35,46 . In our study, neither mtDNA pl content nor platelet function were associated with current or prior ABC-use.…”

Section: Discussionmentioning

confidence: 99%

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

Heijden

Wijer

Jaeger

et al. 2021

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 99%

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

Heijden

Wijer

Jaeger

et al. 2021

Sci Rep

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“…In in vitro experiments, stimulation with abacavir or its metabolite carbovir-triphosphate has been shown to potentiate platelet degranulation and aggregation in response to prothrombotic agonists 89,90 . Mechanistically, stimulation with abacavir or carbovir-triphosphate has been shown to competitively inhibit the activity of guanylyl cyclase when compared to non-guanosine nucleotide analogues, preventing the inhibitory effect of NO, a major negative-regulator of platelet activation 89,90 . Interestingly, we observed increased NO synthesis in platelets from HIV + dengue coinfected patients when compared to patients infected with DENV only.…”

Section: Discussionmentioning

confidence: 99%

Platelet function in HIV plus dengue coinfection associates with reduced inflammation and milder dengue illness

Hottz

Quirino-Teixeira

Valls-de-Souza

et al. 2019

Sci Rep

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HIV-infected subjects under virological control still exhibit a persistent proinflammatory state. Thus, chronic HIV infection changes the host homeostasis towards an adapted immune response that may affect the outcome of coinfections. However, little is known about the impact of HIV infection on inflammatory amplification and clinical presentation in dengue. Platelets have been shown to participate in immune response in dengue and HIV. We hypothesized that altered platelet responses in HIV-infected subjects may contribute to altered inflammatory milieu and disease progression in dengue. We prospectively followed a cohort of 84 DENV-infected patients of whom 29 were coinfected with HIV under virological control. We report that dengue and HIV coinfection progress with reduced inflammation and milder disease progression with lower risk of vascular instability. Even though the degree of thrombocytopenia and platelet activation were similar between dengue-infected and HIV plus dengue-coinfected patients, plasma levels of the platelet-derived chemokines RANTES/CCL5 and PF4/CXCL4 were lower in coinfection. Consistently, platelets from coinfected patients presented defective secretion of the stored-chemokines PF4 and RANTES, but not newly synthesized IL-1β, when cultured ex vivo . These data indicate that platelets from HIV-infected subjects release lower levels of chemokines during dengue illness, which may contribute to milder clinical presentation during coinfection.

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“…Moreover, following oral administration of abacavir, the nitric oxide (NO)-induced increase of platelet cGMP was blunted, potentially explaining the dose-dependent enhancement in platelet aggregation (143,145). While some reports failed to detect stimulatory effects of abacavir on platelets (146,147), most of the aforementioned studies, including those that found that abacavir caused platelet granule release in vitro (148), appear to support the involvement of abacavir in the augmentation of platelet function, both in vitro and in vivo, whereas tenofovir-based therapies had no effect (148). In this context, Taylor et al conclude that "these observations could explain epidemiological and clinical observations linking abacavir with increased incidence of platelet-driven cardiovascular events such as myocardial infarction" (148).…”

Section: Nucleos(t)ide and Non-nucleoside Reverse Transcriptase Inhibmentioning

confidence: 99%

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets

et al. 2021

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Neutrophils are important components of the innate immune system that mediate pathogen defense by multiple processes including phagocytosis, release of proteolytic enzymes, production of reactive oxygen species, and neutrophil extracellular trap formation. Abnormalities of neutrophil count and function have been described in the setting of HIV infection, with the majority of antiretroviral agents (ARVs), excluding zidovudine, having been reported to correct neutropenia. Questions still remain, however, about their impact on neutrophil function, particularly the possibility of persistent neutrophil activation, which could predispose people living with HIV to chronic inflammatory disorders, even in the presence of virally-suppressive treatment. In this context, the effects of protease inhibitors and integrase strand transfer inhibitors, in particular, on neutrophil function remain poorly understood and deserve further study. Besides mediating hemostatic functions, platelets are increasingly recognized as critical role players in the immune response against infection. In the setting of HIV, these cells have been found to harbor the virus, even in the presence of antiretroviral therapy (ART) potentially promoting viral dissemination. While HIV-infected individuals often present with thrombocytopenia, they have also been reported to have increased platelet activation, as measured by an upregulation of expression of CD62P (P-selectin), CD40 ligand, glycoprotein IV, and RANTES. Despite ART-mediated viral suppression, HIV-infected individuals reportedly have sustained platelet activation and dysfunction. This, in turn, contributes to persistent immune activation and an inflammatory vascular environment, seemingly involving neutrophil-platelet-endothelium interactions that increase the risk for development of comorbidities such as cardiovascular disease (CVD) that has become the leading cause of morbidity and mortality in HIV-infected individuals on treatment, clearly underscoring the importance of unraveling the possible etiologic roles of ARVs. In this context, abacavir and ritonavir-boosted lopinavir and darunavir have all been linked to an increased risk of CVD. This narrative review is therefore focused primarily on the role of neutrophils and platelets in HIV transmission and disease, as well as on the effect of HIV and the most common ARVs on the numbers and functions of these cells, including neutrophil-platelet-endothelial interactions.

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Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus‐associated cardiovascular risk

Cited by 26 publications

References 33 publications

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

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

Platelet function in HIV plus dengue coinfection associates with reduced inflammation and milder dengue illness

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets

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