Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Abstract

Cardiovascular diseases and thrombotic events became major clinical problems in the combined antiretroviral therapy (cART) era. Although the precise mechanisms behind these clinical problems have not been fully elucidated, a persistent pro-inflammatory state plays a central role. As platelets play important roles on both, thrombus formation and inflammatory/immune response, we aimed at investigating platelet function in HIV-infected subjects virologically controlled through cART. We evaluate parameters of activation, mitochondrial function and activation of apoptosis pathways in platelets from 30 HIV-infected individuals under stable cART and 36 healthy volunteers. Despite viral control achieved through cART, HIV-infected individuals exhibited increased platelet activation as indicated by P-selectin expression and platelet spreading when adhered on fibrinogen-coated surfaces. Platelets from HIV-infected subjects also exhibited mitochondrial dysfunction and activation of apoptosis pathways. Finally, thrombin stimuli induced lower levels of P-selectin translocation and RANTES secretion, but not TXA2 synthesis, in platelets from HIV-infected individuals compared to control; and labeling of platelet alpha granules showed reduced granule content in platelets from HIV-infected individuals when compared to healthy subjects. In summary, platelets derived from HIV-infected individuals under stable cART exhibit a phenotype of increased activation, activation of the intrinsic pathway of apoptosis and undermined granule secretion in response to thrombin.

Do platelets LINE up for aging?

“…Furthermore, eRT in platelets also serves as a novel mechanism of translational control through the formation of RNA-DNA hybrids. Our findings also support published studies of platelets in HIV, where PLHWA have, in general, evidence of increased platelet activation, mitochondrial stress, and reactive oxygenation species generation [2,3].…”

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

“…We and others have previously shown that platelets from dengue infected patients have features of cellular activation 33–35,39,47,53 . Platelet activation has been also reported in subjects chronically infected with HIV and there is evidence for persistent platelet activation even when virologic suppression is achieved through ART 38,41 . To assess platelet activation in patients coinfected with DENV and HIV-1 we evaluated the surface expression of the activation marker P-selectin (CD62-P) and the synthesis of nitric oxide (NO) in platelets obtained from dengue infected and HIV plus dengue coinfected patients at the febrile and critical phases of dengue illness compared to samples obtained at the recovery.…”

“…We have recently reported that HIV-infected subjects under stable ART have evidence for persistent platelet activation and exhausted platelet α-granules content, even after virological suppression through ART 41 . We therefore hypothesized that exhausted granules in platelets from HIV-infected subjects before coinfection with DENV may affect platelet chemokine secretion during dengue illness resulting in lower levels of platelet-derived chemokines in plasma, as observed in Fig.…”

“…Blood platelets, classically known as specialized cells in hemostasis, are getting increasingly recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system 29–31 . Recently, the contributions of platelets to inflammatory amplification and disease pathogenesis have been identified in both dengue and HIV 32–41 . Even through platelet activation has been extensively investigated in HIV infected subjects and dengue patients, platelet responses in patients co-infected with dengue and HIV were not previously addressed.…”

A Champion of Host Defense: A Generic Large-Scale Cause for Platelet Dysfunction and Depletion in Infection

“… 65 Indeed, platelet activation persists even in virologically suppressed HIV infection. 169 Viral enzymes such as neuraminidase can cause desialylation of platelet surface receptors, 6 and desialylation might promote platelet clearance in the liver. 170 171 …”