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Altered Innate Immune Development in HIV-Exposed Uninfected Infants

Reikie, Brian A. MD*,†; Adams, Rozanne C. M. MSc; Leligdowicz, Aleksandra MD, PhD*; Ho, Kevin BSc*; Naidoo, Shalena MSc; Ruck, Candice E. BSc*; de Beer, Corena PhD§; Preiser, Wolfgang MD, PhD§; Cotton, Mark F. MD, PhD; Speert, David P. MD*; Esser, Monika MD; Kollmann, Tobias R. MD, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2014 - Volume 66 - Issue 3 - p 245–255
doi: 10.1097/QAI.0000000000000161
Basic and Translational Science

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.

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*Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada;

Leaders in Medicine Program, University of Calgary, Calgary, Canada;

Department of Pathology, Immunology Unit, Division of Medical Microbiology, National Health Laboratory Services and Stellenbosch University, Tygerberg, South Africa;

§Department of Pathology, Division of Medical Virology, National Health Laboratory Services and Stellenbosch University, Tygerberg, South Africa; and

Department of Paediatrics and Child Health, Tygerberg Children's Hospital and Stellenbosch University, Tygerberg, South Africa.

Correspondence to: Brian A. Reikie, MD, Department of Pediatrics, Child and Family Research Institute, A5-147, 938 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4 (e-mail:

Supported by the National Institute of Allergy and Infectious Diseases, NIH (N01 AI50023), British Columbia Children's Hospital Foundation, The Martha Piper Fund, the Peter Wall Institute for Advanced Studies, Poliomyelitis Research Foundation, and Harry Crossley Foundation. Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund to T.R.K.; Michael Smith Foundation for Health Research Career Investigator Award to T.R.K; Michael Smith Foundation for Health Research [ST-SGS-02657(09-1)CLIN] to B.A.R; Sauder Family Professor of Pediatric Infectious Diseases to D.P.S; National Health Laboratory Service Research Trust (TY94171) to C.D.B; and National Health Laboratory Service (KNC97 and KNC103) to C.D.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have no conflicts of interest to disclose.

M.E. and T.R.K. contributed equally to this work.

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Received April 03, 2014

Accepted April 03, 2014

© 2014 by Lippincott Williams & Wilkins