HIV‐1 Tat‐induced platelet activation and release of CD154 contribute to HIV‐1‐associated autoimmune thrombocytopenia

Abstract

Summary. Background: Enhanced platelet activation in human immunodeficiency virus (HIV)‐1‐infected patients has been reported and shown to strongly correlate with plasma viral load. Activated platelets are known to express and to release a variety of proteins that can modulate the immune system. Specifically, platelet‐derived CD154 has been shown to be directly involved in the development of autoimmune thrombocytopenia (ITP). The mechanism by which HIV‐1 infection leads to platelet activation and the effect of this activation on the development of HIV‐1 ITP, however, is not fully understood. Objective: We have investigated the effect of HIV‐1 Trans activating factor (Tat) on platelet activation. Results: We report that HIV‐1 Tat directly interacts with platelets and induces platelet activation resulting in platelet micro‐particle release. This activation by Tat requires the chemokine receptor CCR3 and β3‐integrin expression on platelets, as well as calcium flux. Tat‐induced activation of platelets releases platelet CD154, an immune modulator. Enhanced B‐cell activity is found in mouse spleen B cells co‐cultured with platelets treated with Tat in vitro. An early antibody response against adenovirus is found in Tat‐injected mouse immunized with adenovirus, suggesting an enhanced immune response in vivo. Conclusions: We have described a role of Tat‐induced platelet activation in the modulation of the immune system, with implications for the development of HIV‐1‐associated thrombocytopenia.

Excess Soluble CD40L Contributes to Blood Brain Barrier Permeability In Vivo: Implications for HIV-Associated Neurocognitive Disorders

“…Consistently, it has been reported that Tat upregulates molecules known to activate platelets, such as platelet activating factor [57], [58], derived largely from monocytes, which would not be present in the in vitro setting. On the contrary, Wang et al (2011) recently observed that Tat induces direct platelet activation, ultimately leading to the upregulation of surface expressed CD40L on platelets, as measured via flow cytometry [56]. This discrepancy with our previous report [8] may be clarified when considering that Wang et al measured surface expressed CD40L, whereas we measured the soluble form of this molecule.…”

“…Consistent with the data reported herein, Tat has previously been reported to induce platelet activation [56]. Interestingly, we previously demonstrated that treatment of purified platelets with Tat alone did not stimulate the release of sCD40L from these cells, measured via ELISA, indicating that Tat does not directly activate platelets [8].…”

Platelet decline as a predictor of brain injury in HIV infection

“…Platelet interactions with the HIV-1 viral protein, tat, induce activation and expression of CD154 (CD40L) and other platelet-derived immune modulators (Wang et al , 2011). Levels of sCD40L, from activated platelets, are higher in cognitively impaired HIV subjects (Sui et al , 2007).…”

The Impact of HIV Coinfection on Cerebral Malaria Pathogenesis

“…Sequestration may be further enhanced during HIV coinfection via platelet microparticles. HIV-1 Trans-activating factor (Tat) directly interacts with platelets, causing activation and release of platelet microparticles [188]. …”