title: Altered innate immune development in HIV-exposed uninfected infants.
abstract: BACKGROUND
  Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high.
  
  
  METHODS
  A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs).
  
  
  RESULTS
  Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age.
  
  
  CONCLUSIONS
  This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEU infants and may be at least partially responsible for their increased morbidity and mortality from infectious disease.
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.|Leaders in Medicine Program, University of Calgary, Calgary, T2N 4N1, Canada.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Reikie
authors.affiliation: Immunology Unit, Division of Medical Microbiology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Rozanne C M
authors.initials: RCM
authors.lastname: Adams
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Leligdowicz
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Ho
authors.affiliation: Immunology Unit, Division of Medical Microbiology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Shalena
authors.initials: S
authors.lastname: Naidoo
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
authors.forename: Candice E
authors.initials: CE
authors.lastname: Rusk
authors.affiliation: Division of Medical Virology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Corena
authors.initials: C
authors.lastname: de Beer
authors.affiliation: Division of Medical Virology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Preiser
authors.affiliation: Department of Paediatrics and Child Health, Tygerberg Children's Hospital and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Speert
authors.affiliation: Immunology Unit, Division of Medical Microbiology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
authors.forename: Monika
authors.initials: M
authors.lastname: Esser
authors.affiliation: Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Kollmann
mesh_terms: D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission; D018023:HIV Seronegativity / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007231:Infant, Newborn / Q000276:immunology*; D018445:Infectious Disease Transmission, Vertical; D008137:Longitudinal Studies; D008297:Male; D009000:Monocytes / Q000276:immunology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology* / Q000821:virology; D011446:Prospective Studies; D013019:South Africa
chemical_list: D016207:Cytokines
references.citation: Clin Immunol. 2009 Nov;133(2):228-37
references.pmid: 19648060
references.citation: PLoS One. 2010 Apr 28;5(4):e10407
references.pmid: 20442853
references.citation: J Immunotoxicol. 2008 Oct;5(4):401-12
references.pmid: 19404874
references.citation: Lancet Infect Dis. 2012 Apr;12(4):330-40
references.pmid: 22364680
references.citation: Front Immunol. 2013 Apr 02;4:81
references.pmid: 23565115
references.citation: J Acquir Immune Defic Syndr. 2006 Aug 15;42(5):545-53
references.pmid: 16837862
references.citation: Cytometry A. 2006 Sep 1;69(9):1037-42
references.pmid: 16888771
references.citation: PLoS One. 2011 Mar 31;6(3):e18319
references.pmid: 21483827
references.citation: Epidemiology. 1990 Jan;1(1):43-6
references.pmid: 2081237
references.citation: J Acquir Immune Defic Syndr. 2006 Apr 1;41(4):504-8
references.pmid: 16652060
references.citation: J Immunol Methods. 2008 Jul 31;336(2):183-92
references.pmid: 18565537
references.citation: Bioinformatics. 2012 Apr 1;28(7):1009-16
references.pmid: 22383736
references.citation: Cytometry A. 2010 Jun;77(6):546-51
references.pmid: 20131398
references.citation: Pediatr Infect Dis J. 2011 Jan;30(1):45-51
references.pmid: 21173675
references.citation: Lancet. 2005 Mar 26-Apr 1;365(9465):1147-52
references.pmid: 15794969
references.citation: Cytometry A. 2008 Oct;73(10):926-30
references.pmid: 18752282
references.citation: J Infect Dis. 2000 May;181(5):1590-7
references.pmid: 10823758
references.citation: Lancet. 2003 Jun 28;361(9376):2226-34
references.pmid: 12842379
references.citation: PLoS One. 2011 Apr 13;6(4):e18185
references.pmid: 21533209
references.citation: Clin Infect Dis. 2010 Feb 1;50(3):445-7
references.pmid: 20047482
references.citation: AIDS. 1998 Oct 1;12(14):1805-13
references.pmid: 9792381
references.citation: Pediatr Infect Dis J. 2007 Jun;26(6):519-26
references.pmid: 17529870
references.citation: Immunity. 2012 Nov 16;37(5):771-83
references.pmid: 23159225
references.citation: J Immunol. 2006 Mar 15;176(6):3742-52
references.pmid: 16517743
references.citation: PLoS Pathog. 2011 Aug;7(8):e1002174
references.pmid: 21852947
references.citation: Trop Med Int Health. 2009 Mar;14(3):276-87
references.pmid: 19171011
references.citation: N Engl J Med. 1993 Dec 2;329(23):1696-702
references.pmid: 8232458
references.citation: Pediatr Allergy Immunol. 2010 Sep;21(6):977-82
references.pmid: 20718928
references.citation: Clin Immunol. 2011 Mar;138(3):299-310
references.pmid: 21247809
references.citation: Clin Immunol. 2008 Mar;126(3):243-50
references.pmid: 18201932
references.citation: J Infect Dev Ctries. 2012 Feb 13;6(2):109-19
references.pmid: 22337838
references.citation: AIDS. 2013 Mar 13;27(5):749-59
references.pmid: 23719347
references.citation: AIDS. 2005 Jul 1;19(10):1071-9
references.pmid: 15958839
references.citation: Pediatrics. 2010 Sep;126(3):e631-8
references.pmid: 20732944
references.citation: J Nutr. 2008 Sep;138(9):1782S-1790S
references.pmid: 18716187
references.citation: Acta Paediatr. 2005 Nov;94(11):1571-7
references.pmid: 16303696
references.citation: Lancet. 2000 Feb 5;355(9202):451-5
references.pmid: 10841125
references.citation: Bull World Health Organ. 2008 May;86(5):408-16
references.pmid: 18545744
references.citation: Expert Rev Clin Pharmacol. 2011 Mar;4(2):275-89
references.pmid: 21643519
references.citation: PLoS One. 2012;7(9):e44763
references.pmid: 23028609
references.citation: Environ Health Perspect. 2009 May;117(5):845-9
references.pmid: 19478971
references.citation: PLoS One. 2012;7(5):e36793
references.pmid: 22649499
references.citation: J Acquir Immune Defic Syndr. 2010 Dec;55(4):428-38
references.pmid: 20838227
references.citation: J Immunol Methods. 2011 Mar 7;366(1-2):89-99
references.pmid: 21277305
references.citation: J Trop Pediatr. 2012 Dec;58(6):505-8
references.pmid: 22555385
references.citation: PLoS One. 2010 Nov 30;5(11):e15041
references.pmid: 21152080
references.citation: Front Immunol. 2012 Dec 31;3:399
references.pmid: 23293640