title: Regulatory T cells and the risk of CMV end-organ disease in patients with AIDS.
abstract: OBJECTIVE
  Cytomegalovirus (CMV)-specific T-cell effectors (CMV-Teff) protect against CMV end-organ disease (EOD). In HIV-infected individuals, their numbers and function vary with CD4 cell numbers and HIV load. The role of regulatory T cells (Treg) in CMV-EOD has not been extensively studied. We investigated the contribution of Treg and Teff toward CMV-EOD in HIV-infected individuals independently of CD4 cell numbers and HIV load and controlling for CMV reactivations.
  
  
  METHODS
  We matched 43 CMV-EOD cases to 93 controls without CMV-EOD, but with similar CD4 cell numbers and HIV plasma RNA. CMV reactivation was investigated by blood DNA polymerase chain reaction over 32 weeks preceding the CMV-EOD in cases and preceding the matching point in controls.
  
  
  METHODS
  CMV-Teff and Treg were characterized by the expression of interferon-γ (IFN-γ), interleukin 2, tumor necrosis factor α (TNFα), MIP1β, granzyme B (GrB), CD107a, TNFα, FOXP3, and CD25.
  
  
  RESULTS
  Sixty-five percent cases and 20% controls had CMV reactivations. In multivariate analyses that controlled for CMV reactivations, none of the CMV-Teff subsets correlated with protection, but high CMV-GrB enzyme-linked immunosorbent spot responses and CMV-specific CD4FOXP3+%, CD4TNFα+%, and CD8CD107a% were significant predictors of CMV-EOD.
  
  
  CONCLUSIONS
  Because both FOXP3 and GrB have been previously associated with Treg activity, we conclude that CMV-Treg may play an important role in the development of CMV-EOD in advanced HIV disease. We were not able to identify a CMV-Teff subset that could be used as a surrogate of protection against CMV-EOD in this highly immunocompromised population.
authors.affiliation: *Department of Pediatric Medicine and Pathology, School of Medicine, University of Colorado Denver, Aurora, CO; †Department of Biostatistics, Harvard School of Public Health, Boston, MA; ‡Division of Infectious Diseases, School of Medicine, University of San Diego, San Diego, CA; §Division of Allergy and Infectious Diseases, School of Medicine, Harborview Medical Center and the University of Washington School of Medicine, Seattle, WA; ‖Department of Infectious Diseases, School of Medicine, University of Stanford, Stanford, CA; ¶Department of Medicine, Division of Infectious Diseases, Weill Medical College of Cornell University, New York, NY; #Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; **Department of Medicine, St. Luke's-Roosevelt Medical Center and Columbia University College of Physicians and Surgeons, New York, NY; ††Servicio de Medicina Interna, Hospital Asepeyo Coslada, Madrid, Spain; and ‡‡Department of Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Weinberg
authors.forename: Ronald
authors.initials: R
authors.lastname: Bosch
authors.forename: Kara
authors.initials: K
authors.lastname: Bennett
authors.forename: Adriana
authors.initials: A
authors.lastname: Tovar-Salazar
authors.forename: Constance A
authors.initials: CA
authors.lastname: Benson
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Andrew
authors.initials: A
authors.lastname: Zolopa
authors.forename: Roy M
authors.initials: RM
authors.lastname: Gulick
authors.forename: David
authors.initials: D
authors.lastname: Wohl
authors.forename: Bruce
authors.initials: B
authors.lastname: Polsky
authors.forename: Alejo
authors.initials: A
authors.lastname: Erice
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003586:Cytomegalovirus Infections / Q000453:epidemiology* / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*