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Abstract
Despite the use of highly active antiretroviral therapies (HAART), a majority of Human Immunodeficiency Virus Type 1 (HIV) infected individuals continually develop HIV – Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistent with this notion, we have previously shown that levels of the inflammatory mediator soluble CD40 ligand (sCD40L) are elevated in the plasma and cerebrospinal fluid (CSF) of HIV infected, cognitively impaired individuals, and that excess sCD40L can contribute to blood brain barrier (BBB) permeability in vivo, thereby signifying the importance of this inflammatory mediator in the pathogenesis of HAND. Here we demonstrate that the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) induces the release of circulating sCD40L in both HIV infected individuals and in an in vitro suspension of washed human platelets, which are the main source of circulating sCD40L. Additionally, EFV was found to activate glycogen synthase kinase 3 beta (GSK3β) in platelets, and we now show that valproic acid (VPA), a known GSK3β inhibitor, was able to attenuate the release of sCD40L in HIV infected individuals receiving EFV, and in isolated human platelets. Collectively these results have important implications in determining the pro-inflammatory role that some antiretroviral regimens may have. The use of antiretrovirals remains the best strategy to prevent HIV-associated illnesses, including HAND, however these drugs have clear limitations to this end, and thus, these results underscore the need to develop adjunctive therapies for HAND that can also minimize the undesired negative effects of the antiretrovirals.
Highlights
Human Immunodeficiency Virus Type 1 (HIV) – Associated Neurocognitive Disorders (HAND) are found in approximately 50% of infected individuals [1] and are associated with the loss of normal neuron function leading to behavioral, motor, and cognitive deficiencies [2,3,4,5]
Despite the use of highly active antiretroviral therapies (HAART), which are able to efficiently control viral load, the prevalence of these disorders continues to rise as individuals live longer and more people are exposed to the current therapies [1], which largely fail to control the viral impact on the central nervous system (CNS)
Consistent with this notion, we previously demonstrated that the inflammatory mediator soluble CD40 ligand, is present at significantly higher levels in both plasma and cerebrospinal fluid (CSF) samples of HIV infected, cognitively impaired individuals [7] as compared to their infected, non-cognitively impaired counterpart
Summary
Human Immunodeficiency Virus Type 1 (HIV) – Associated Neurocognitive Disorders (HAND) are found in approximately 50% of infected individuals [1] and are associated with the loss of normal neuron function leading to behavioral, motor, and cognitive deficiencies [2,3,4,5]. Infiltration of the CNS by activated monocytic cells through a compromised blood brain barrier (BBB) is believed to be the main factor involved in neuronal dysfunction, which occurs as a result of excess inflammation in the brain that is progressively neurotoxic [6] Consistent with this notion, we previously demonstrated that the inflammatory mediator soluble CD40 ligand (sCD40L; known as CD154), is present at significantly higher levels in both plasma and cerebrospinal fluid (CSF) samples of HIV infected, cognitively impaired individuals [7] as compared to their infected, non-cognitively impaired counterpart. We recently reported that the HIV transactivator of transcription (Tat) alone is sufficient to stimulate the release of sCD40L in vivo, in a manner that promoted increased BBB permeability [8] This effect was found to be CD40L-dependent and required the presence of platelets, the main source of sCD40L [8,9]. It was recently demonstrated that the receptor for CD40L, CD40, is upregulated during HIV infection, presumably via exposure to Tat [7], in a manner that promotes brain microvascular endothelial cell activation, monocyte re-
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