Elucidating the Role of Soluble CD40 Ligand in the Pathogenesis of HIV-Associated Neurocognitive Disorders (HAND).

摘要

Human Immunodeficiency Virus Type 1 (HIV) continues to be one of the largest global health afflictions to date. The advent and introduction of combined antiretroviral therapy (cART) has made a significant impact on the course of infection, dramatically extending the average lifespan of HIV infected individuals. However, as these individuals are living longer, many HIV-associated illnesses are becoming prevalent among the infected population, especially those associated with chronic inflammation. Consistently, HIV-Associated Neurocognitive Disorders (HAND) are estimated to persist in approximately 50% of infected individuals regardless of cART, underscoring the need to develop effective adjunctive therapies for these disorders, which are currently lacking.;We previously demonstrated that the pro-inflammatory mediator soluble CD40 ligand (sCD40L) is elevated in the plasma and cerebrospinal fluid of HIV infected, cognitively impaired individuals as compared to infected, non-impaired counterparts. In an effort to determine whether sCD40L is contributing to the pathogenesis of HAND, we employed quantitative analyses of blood brain barrier (BBB) permeability, as well as complementary multiphoton microscopy in both wild-type (WT) and CD40L-deficient mice in the context of HIV infection. The data presented herein demonstrate that excess sCD40L contributes to BBB permeability and an increase in leukocyte attachment to the brain microvasculature. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets.;In order to determine whether plasma concentrations of sCD40L could be modulated in vivo, we investigated the ability of the mood-stabilizing drug valproic acid (VPA) to attenuate sCD40L release in HIV infected patients and in washed human platelets, the main source of sCD40L. VPA significantly reduced sCD40L concentrations in the plasma of infected individuals and inhibited the release of sCD40L directly from platelets via GSK3β inhibition, and subsequent attenuation of platelet cytoskeletal rearrangement. These data reveal that VPA possesses antiplatelet activity, and convey important implications for the potential of VPA as an adjunctive therapy not only for HAND, but also for numerous inflammatory diseases.;Previous reports suggest that some common antiretrovirals can induce inflammation; thus, we sought to determine whether these drugs contribute to the excess sCD40L concentrations found in HAND individuals. Our results demonstrate that non-nucleoside reverse transcriptase inhibitors (NNRTI), but not other classes of antiretrovirals, induce the release of sCD40L in both HIV infected individuals, and in isolated human platelets. Treatment with VPA attenuated the release of sCD40L in HIV infected individuals receiving cART with an NNRTI, and in washed platelets. Collectively, these results emphasize the need to develop adjunctive therapies for HAND that can also minimize the negative effects of cART, and further highlight the potential benefit of VPA, or alternative antiplatelet agents, as such.;As a whole, our results expound the role of sCD40L, and thus platelet activation, in the pathogenesis of HAND, thereby implicating sCD40L as a major contributing factor in the loss of vascular integrity in the context of disease. Furthermore, this work highlights the utility of antiplatelet therapy as a novel therapeutic approach for the management of HAND and HIV-associated inflammation.