Abstract
Human immunodeficiency virus type 1 (HIV) continues to be one of the most prevalent global health afflictions to date. The advent and introduction of combined antiretroviral therapy (cART) has made a significant impact on the course of infection. However, as patients are living longer, many HIV-associated illnesses are becoming prevalent among the infected population, especially those associated with chronic inflammation. Consistently, HIV-associated neuroinflammation is believed to be a major catalyst in the development of HIV-associated neurocognitive disorders (HAND), which are estimated to persist in approximately 50% of infected individuals regardless of cART. This dramatically underscores the need to develop effective adjunctive therapies capable of controlling this aspect of the disease, which are currently lacking.We previously demonstrated that the inflammatory mediator soluble CD40 ligand (sCD40L) is elevated in both the plasma and cerebrospinal fluid of cognitively impaired infected individuals compared to their non-impaired infected counterparts. Our group, and others have recently demonstrated that there is an increasing role for this inflammatory mediator in the pathogenesis of HIV-associated neuroinflammation, thereby identifying this molecule as a potential therapeutic target for the management of HAND. Platelets are the major source of circulating sCD40L, and these small cells are increasingly implicated in a multitude of inflammatory disorders, including those common during HIV infection. Thus, antiplatelet therapies that minimize the release of platelet-derived inflammatory mediators such as sCD40L are an innovative, non-traditional approach for the treatment of HIV-associated neuroinflammation, with the potential to benefit other HIV-associated illnesses.
Highlights
CD40 ligand (CD40L, formally known as CD154) is a type II membrane glycoprotein of the tumor necrosis factor (TNF) family that is found on activated T cells, B cells and platelets [1]
While there are many factors, both host derived and viral, that orchestrate the breakdown of the blood–brain barrier (BBB) during Human immunodeficiency virus type 1 (HIV) infection [25,27,28,29,30], we observed a drastic effect mediated by platelet-derived CD40L. These results suggest that the CD40L/CD40 pair has a large role in the progression of HIV-associated neurocognitive disorders (HAND), and provide evidence that excessive platelet activation may be contributing to a multitude of other inflammatory disorders
Platelet activation and the CD40/ CD40L axis have been reported to have induced vascular permeability in ischemia/reperfusion injury in the brain [56], as well as other disorders of the central nervous system (CNS), notably cerebral malaria [19,57,58]. These studies have taken advantage of both platelet depletion and/or CD40or CD40L-deficient mouse models to demonstrate that CD40L signaling is required for the breakdown of the BBB and consequential tissue damage. These results are consistent with our previous findings, and further highlight the unconventional role of platelet activation and the subsequent release of soluble CD40 ligand (sCD40L) in the progression of diseases known to be exacerbated by vascular permeability in both the periphery and the CNS
Summary
CD40 ligand (CD40L, formally known as CD154) is a type II membrane glycoprotein of the tumor necrosis factor (TNF) family that is found on activated T cells, B cells and platelets [1]. These studies have taken advantage of both platelet depletion and/or CD40or CD40L-deficient mouse models to demonstrate that CD40L signaling is required for the breakdown of the BBB and consequential tissue damage These results are consistent with our previous findings, and further highlight the unconventional role of platelet activation and the subsequent release of sCD40L in the progression of diseases known to be exacerbated by vascular permeability in both the periphery and the CNS. The use of antiplatelet agents that can attenuate the release of sCD40L from platelets, while leaving surfaceexpressed co-stimulatory CD40L unaltered, would prevent the negative effects on the humoral immune response, and represents an attractive alternative therapeutic strategy with broad implications for a wide range of inflammatory disorders To this end, it is an interesting notion that antiplatelet agents, which are traditionally used for the management of cardiovascular disease or inflammation in the periphery, could be used to treat neurological disorders.
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