Abstract
Highly active antiretroviral therapy (HAART) has made a significant impact on the lives of people living with HIV-1 infection. The incidence of neurologic disease associated with HIV-1 infection of the CNS plummeted between 1996–2000, but unfortunately the number of people currently HIV-1 infected (i.e., prevalence) with associated cognitive impairment has been steadily rising. While the reasons for this may be multifactorial, the implication is clear: there is a pressing need for adjunctive therapy directed at reversing or preventing damage to vulnerable pathways in the central nervous system (CNS) from HIV-1 infection. Using a team of preclinical and clinical investigators, we have focused our efforts on defining how proinflammatory mediators and secretory neurotoxins from HIV-1 disrupt signaling of the survival-regulating enzyme, glycogen synthase kinase 3 beta (GSK-3β). In a series of studies initiated using in vitro, then in vivo models of HIV-1-associated dementia (HAD), we have demonstrated the ability of the mood stabilizing and anticonvulsant drug, sodium valproate (VPA), that inhibits GSK-3β activity and other downstream mediators, to reverse HIV-1-induced damage to synaptic pathways in the CNS. Based on these results, we successfully performed pharmacokinetic and safety and tolerability trials with VPA in a cohort of HIV-1-infected patients with neurologic disease. VPA was well tolerated in this population and secondary measures of brain metabolism, as evidenced by an increase in N-acetyl aspartate/creatine (NAA/Cr), further suggested that VPA may improve gray matter integrity in brain regions damaged by HIV-1. These findings highlight the therapeutic potential of GSK-3β blockade.
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Acknowledgements
The investigative team for this work encompassed three institutions: S. Dewhurst, S. Maggirwar, D. Peterson, G. Schifitto, R. J. Zhong, and H.A. Gelbard of the University of Rochester Medical Center, R. DiCenzo and G. Morse at the State University of Buffalo, and H. Dou, M. Boska, and H. Gendelman of the University of Nebraska Medical Center. We would also like to acknowledge the generous support of the Geoffrey Waasdorp Pediatric Neurology Fund, University of Rochester Medical Center. This work was supported by NIH grants PO1 MH64570, R01 MH56838, and RO1 NS054578.
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Dewhurst, S., Maggirwar, S.B., Schifitto, G. et al. Glycogen Synthase Kinase 3 Beta (GSK-3β) as a Therapeutic Target in NeuroAIDS. Jrnl Neuroimmune Pharm 2, 93–96 (2007). https://doi.org/10.1007/s11481-006-9051-1
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DOI: https://doi.org/10.1007/s11481-006-9051-1