Journal of NeuroVirology, 11: 535–543, 2005 c  2005 Journal of NeuroVirology ISSN: 1355-0284 print / 1538-2443 online DOI: 10.1080/13550280500385203 Aquaporin 4 is increased in association with human immunodeficiency virus dementia: Implications for disease pathogenesis Coryse St Hillaire, 1 Diana Vargas, 1 Carlos A Pardo, 1,2 Dan Gincel, 1 Jacquelyn Mann, 1 Jeffrey D Rothstein, 1,3 Justin C McArthur, 1,4 and Katherine Conant 1 Departments of 1 Neurology, 2 Neuropathology, and 3 Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 4 Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA Changes in astrocyte shape and function are known to occur in association with human immunodeficiency virus (HIV) dementia (HIVD). However, the causes and consequences of such changes are not completely understood. In vitro data suggest that changes in the expression of aquaporin 4 (AQP4), the aquaporin subtype expressed by astrocytes, can significantly influence cell shape and physiology. In the present study, the authors therefore investigated the possi- bility that AQP4 levels may be altered in HIVD. Using Western blot, the authors show that immunoreactivity for AQP4 is elevated in brain homogenates from the mid frontal gyrus of patients who died with HIVD (P < .005 HIV seroneg- ative versus HIVD). Of interest, a significant increase was also observed in homogenates from HIV-infected individuals without dementia (P < .05 HIV seronegative versus neurologically normal HIV seropositive). In the present study the authors also examined the stimulated expression of AQP4 in cul- tured cells. Previous in vitro studies have shown that AQP4 expression may be increased by stimuli that induce cytoskeletal changes and/or the activation of p38 mitogen-activated protein (MAP) kinase. The authors therefore focused on tumor necrosis factor (TNF)-α, which has been linked to p38 MAP kinase ac- tivation, and thrombin, which may also induce changes in the actin cytoskele- ton. Both may be elevated with HIVD. Again using Western blot, the authors show an increase in both AQP4 and phosphorylated p38 MAP kinase in ho- mogenates from TNF-α- and thrombin-stimulated organotypic cerebellar and spinal cord cultures. Together, these studies suggest that AQP4 expression may be altered in HIVD and/or in response to exogenous proteinases. Additional studies may be warranted to determine whether altered AQP4 expression rep- resents a protective and/or maladaptive response to central nervous system (CNS) inflammation. Journal of NeuroVirology (2005) 11, 535–543. Keywords: aquaporin; astrocytes; dementia; HIV; thrombin Address correspondence to Dr. Conant, Department of Neu- rology, Meyer 6-109, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA. E-mail: kconant@jhmi. edu The authors would like to thank Liping Guo for immunohisto- chemistry, Dr. Anita Venkakatarama for assistance with diagnostic criteria, and Drs. Daniel Gorelick and Peter Agre for anti-AQP4. This work was funded by the National Institutes of Health (MH 07028901 and NS44897 to KC and JCM, respectively). Received 6 April 2005; revised 3 August 2005; accepted 25 September 2005. Introduction Our understanding of those events that are criti- cal to the development of human immunodeficiency virus (HIV)–1–associated dementia (HIVD) is lim- ited, but inflammation within the central nervous system (CNS) is thought to play an important role. HIVD typically occurs late in the course of HIV disease, when the specific immune response is im- paired and the nonspecific is relatively activated.