Differential Responsiveness of the Platelet Biomarkers, Systemic CD40 Ligand, CD62P, and Platelet-Derived Growth Factor-BB, to Virally-Suppressive Antiretroviral Therapy.

Helen C Steel,Natasha Arulappan,Ronald Anderson,Annette J Theron,Charles Feldman,Theresa M Rossouw,W D Francois Venter

doi:10.3389/fimmu.2020.594110

Abstract

Systemic biomarkers of inflammation, including cytokines and chemokines, are potentially useful in the management of both HIV infection and non-AIDS-defining disorders. However, relatively little is known about the utility of measurement of circulating biomarkers of platelet activation as a strategy to monitor the efficacy of combination antiretroviral therapy (cART), as well as the persistence of systemic inflammation following virally-suppressive therapy in HIV-infected persons. These issues have been addressed in the current study to which a cohort consisting of 199 HIV-infected participants was recruited, 100 of whom were cART-naïve and the remainder cART-treated and virally-suppressed. Fifteen healthy control participants were included for comparison. The study focused on the effects of cART on the responsiveness of three biomarkers of platelet activation, specifically soluble CD40 ligand (sCD40L), sCD62P (P-selectin), and platelet-derived growth factor-BB (PDGF-BB), measured using multiplex suspension bead array technology. Most prominently sCD40L in particular, as well as sCD62P, were significantly elevated in the cART-naïve group relative to both the cART-treated and healthy control groups. However, levels of PDGF-BB were of comparable magnitude in both the cART-naïve and –treated groups, and significantly higher than those of the control group. Although remaining somewhat higher in the virally-suppressed group relative to healthy control participants, these findings identify sCD40L, in particular, as a potential biomarker of successful cART, while PDGF-BB may be indicative of persistent low-level antigenemia.

Highlights

It is well recognized that activated platelets play a fundamental role in thrombosis, and in inflammation, via release of prostanoids, especially thromboxane A2, as well as expressed and granule-packaged, pre-formed, pro-inflammatory proteins such as the adhesion receptor, CD40 ligand (CD40L) [1, 2]
Participants had started on combination antiretroviral therapy (cART) a median of 14 (IQR 14–19) months earlier, and all had an undetectable viral load (VL) (≤40 copies/ml) at the time of the study
Our findings demonstrate that the concentrations of the three test biomarkers associated with platelet activation, soluble CD40 ligand (sCD40L), sCD62P, and plateletderived growth factor-BB (PDGF-BB), all of which are located in the a-granules [28], TABLE 3 | Univariate analysis

Summary

Introduction

It is well recognized that activated platelets play a fundamental role in thrombosis, and in inflammation, via release of prostanoids, especially thromboxane A2, as well as expressed and granule-packaged, pre-formed, pro-inflammatory proteins such as the adhesion receptor, CD40 ligand (CD40L) [1, 2]. CART has been shown to effectively increase platelet counts following 3 months of treatment, platelet activation persists, possibly because of microbial translocation, resulting in sustained exposure of these cells to microbial components in the circulation [5,6,7,8,9] In this setting, platelet activation is likely to be the leading cause of elevated levels of circulating sCD40L detected during chronic HIV infection [1]. It is noteworthy that sCD40L possesses several pro-inflammatory/prothrombotic interactions with neutrophils and macrophages that have been linked to the etiology of acute and chronic cardiovascular disorders [10,11,12,13] In this context, many of the long-term complications in HIV-infected individuals, such as ischemic thrombosis, which is one of the most common causes of death among virally-suppressed persons [14], have been associated with platelet activation [15]

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Discussion

Conclusion