title: Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders.
abstract: FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p < 0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p = 0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p = 0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. vsoontor@ucsd.edu
authors.forename: Virawudh
authors.initials: V
authors.lastname: Soontornniyomkij
authors.forename: Ian P
authors.initials: IP
authors.lastname: Everall
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Ben
authors.initials: B
authors.lastname: Gouaux
authors.forename: Erick T
authors.initials: ET
authors.lastname: Tatro
authors.forename: Vadim
authors.initials: V
authors.lastname: Gospodarev
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Yin
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Cristian L
authors.initials: CL
authors.lastname: Achim
mesh_terms: D015526:AIDS Dementia Complex / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D016174:Hepacivirus / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D020534:Parahippocampal Gyrus / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D019966:Substance-Related Disorders / Q000150:complications / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D044966:Anti-Retroviral Agents; D008694:Methamphetamine; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5