title: Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.
abstract: BACKGROUND
  Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI).
  
  
  METHODS
  Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF.
  
  
  RESULTS
  A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively.
  
  
  CONCLUSIONS
  Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.
authors.affiliation: Yale School of Medicine, 367 Cedar Street, New Haven, CT 06510, USA. joome.suh@yale.edu.
authors.forename: Joome
authors.initials: J
authors.lastname: Suh
authors.affiliation: Department of Medicine, UCSF School of Medicine, 1001 Potrero Avenue, SFGH 100, San Francisco, CA, 94143, USA. esinclair@sfgh.ucsf.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: Department of Neurology, UCSF School of Medicine, 1001 Potrero Avenue, SFGH 1, San Francisco, CA, 94110, USA. julia.eve.peterson@gmail.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Department of Neurology, UCSF School of Medicine, 1001 Potrero Avenue, SFGH 1, San Francisco, CA, 94110, USA. elee@mghihp.edu.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lee
authors.affiliation: Yale Center for Analytical Sciences, Yale University, 300 George Street, Suite 555, New Haven, CT 06520, USA. tassos.kyriakides@yale.edu.
authors.forename: Tassos C
authors.initials: TC
authors.lastname: Kyriakides
authors.affiliation: Yale Center for Analytical Sciences, Yale University, 300 George Street, Suite 555, New Haven, CT 06520, USA. fang-yong.li@yale.edu.
authors.forename: Fang-Yong
authors.initials: FY
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Journalvägen 10, 416 85, Gothenburg, Sweden. lars.hagberg@medfak.gu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Hagberg
authors.affiliation: Division of Biological Chemistry, Innsbruck Medical University, Innrain 80, 6020, Innsbruck, Austria. dietmar.fuchs@i-med.ac.at.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Neurology, UCSF School of Medicine, 1001 Potrero Avenue, SFGH 1, San Francisco, CA, 94110, USA. rwprice@sfgh.ucsf.edu.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Price
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Journalvägen 10, 416 85, Gothenburg, Sweden. magnus.gisslen@infect.gu.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gisslen
authors.affiliation: Department of Neurology, Yale School of Medicine, 300 George Street, Room 8300c, New Haven, CT 06510, USA. serena.spudich@yale.edu.
authors.forename: Serena
authors.initials: S
authors.lastname: Spudich
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007110:Immunity, Active / Q000276:immunology*; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood / Q000134:cerebrospinal fluid; D019562:Viral Load / Q000276:immunology
chemical_list: D015415:Biomarkers; D019798:Neopterin