title: Evidence of the innate antiviral and neuroprotective properties of progranulin.
abstract: BACKGROUND
  Compelling data exist that show that normal levels of progranulin (PGRN) are required for successful CNS aging. PGRN production is also modulated by inflammation and infection, but no data are available on the production and role of PGRN during CNS HIV infection.
  
  
  METHODS
  To determine the relationships between PGRN and HIV disease, neurocognition, and inflammation, we analyzed 107 matched CSF and plasma samples from CHARTER, a well-characterized HIV cohort. Levels of PGRN were determined by ELISA and compared to levels of several inflammatory mediators (IFNγ, IL-6, IL-10, IP-10, MCP-1, TNFα, IL-1β, IL-4 and IL-13), as well as clinical, virologic and demographic parameters. The relationship between HIV infection and PGRN was also examined in HIV-infected primary human microglial cultures.
  
  
  RESULTS
  In plasma, PGRN levels correlated with the viral load (VL, p<0.001). In the CSF of subjects with undetectable VL, lower PGRN was associated with neurocognitive impairment (p = 0.046). CSF PGRN correlated with CSF IP-10, TNFα and IL-10, and plasma PGRN correlated with plasma IP-10. In vitro, microglial HIV infection increased PGRN production and PGRN knockdown increased HIV replication, demonstrating that PGRN is an innate antiviral protein.
  
  
  CONCLUSIONS
  We propose that PGRN plays dual roles in people living with HIV disease. With active HIV replication, PGRN is induced in infected macrophages and microglia and functions as an antiviral protein. In individuals without active viral replication, decreased PGRN production contributes to neurocognitive dysfunction, probably through a diminution of its neurotrophic functions. Our results have implications for the pathogenesis, biomarker studies and therapy for HIV diseases including HIV-associated neurocognitive dysfunction (HAND).
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Hyeon-Sook
authors.initials: HS
authors.lastname: Suh
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Yungtai
authors.initials: Y
authors.lastname: Lo
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Namjong
authors.initials: N
authors.lastname: Choi
authors.affiliation: Department of Neurology, University of California San Diego, San Diego, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000328:Adult; D003071:Cognition; D005260:Female; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000821:virology; D015999:Multivariate Analysis; D000077153:Progranulins; D019562:Viral Load; D014779:Virus Replication
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins