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Regulatory T Cells in HIV-Infected Immunological Nonresponders Are Increased in Blood but Depleted in Lymphoid Tissue and Predict Immunological Reconstitution

Gaardbo, Julie C. MD*,†; Hartling, Hans J. MD*,†; Ronit, Andreas*,†; Springborg, Karoline MD; Gjerdrum, Lise M. R. MD§; Ralfkiær, Elisabeth§; Thorsteinsson, Kristina MD; Ullum, Henrik MD, PhD; Andersen, Åse B.; Nielsen, Susanne D.*

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1st, 2014 - Volume 66 - Issue 4 - p 349–357
doi: 10.1097/QAI.0000000000000173
Basic and Translational Science

Background: HIV-infected immunological nonresponders fail to immune reconstitute despite optimal treatment. We hypothesized that regulatory T cells (Tregs) are involved in immunological reconstitution. Tregs and Treg subpopulations were measured in blood and Foxp3+ cells in lymphoid tissue, and the impact of Tregs on immunological reconstitution was determined.

Methods: HIV-infected individuals on combination antiretroviral therapy for a minimum of 2 years were included. The study population included 14 immunological nonresponders (INR; CD4 T-cell count <200 cells/μL), 33 intermediate responders (CD4 T-cell count 200–500 cells/μL), 30 responders (CD4 T-cell count >500 cells/μL), and 34 healthy controls. Tregs, Treg subpopulations, and intracellular staining for interleukin 10 in peripheral blood were measured using flow cytometry. Foxp3+ cells in lymphoid tissue were evaluated using immunolabeling. The CD4 T-cell count was determined at inclusion and after 1 year of follow-up.

Results: INR displayed high percentage of Tregs and activated Tregs in peripheral blood accompanied by a high percentage of Tregs expressing interleukin 10, whereas numbers of Foxp3+ cells in lymphoid tissue were low. In contrast, responders resembled healthy controls. Finally, in INR, high level of Tregs in blood and Foxp3+ cells in lymphoid tissue were associated with higher level of immunological reconstitution after 1 year of follow-up.

Conclusions: In conclusion, altered distribution of Tregs was found in INR. Interestingly, high level of Tregs predicted higher level of immunological reconstitution suggesting a role for Tregs in immunological reconstitution.

*Viro-immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark;

Departments of Clinical Immunology;

Otorhinolaryngology;

§Pathology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark;

Department of Infectious Diseases, Hvidovre Hospital, University Hospital of Copenhagen, Copenhagen, Denmark; and

Department of Infectious Diseases, Odense Hospital, University of Southern Denmark, Odense, Denmark.

Correspondence to: Susanne D. Nielsen, Department of Infectious Diseases M5132, Rigshospitalet, Blegdamsvej 9B, Copenhagen-2100, Denmark (e-mail: sdn@dadlnet.dk).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Supported by University of Copenhagen, Novo Nordisk Foundation, Lundbeck Foundation, Rigshospitalet Research Council, Augustinus Foundation, The Danish AIDS Foundation, and Danish Medical Association. J.C.G. and S.D.N. received research funding from University of Copenhagen, the Novo Nordisk Foundation, the Augustinus Foundation, and the Danish Medical Association.

Part of the results was presented at 13th European AIDS Conference/EACS, October 2011 (PS12/2).

The authors have no conflicts of interest to disclose.

J.C.G. designed the study, included the patients, performed the experiments, analyzed the results and wrote the manuscript. H.J.H. included the patients, performed the experiments and critically revised the manuscript. A.R. included the patients, performed the experiments and critically revised the manuscript. K.S. performed the tonsil biopsies and critically revised the manuscript, L.M.R.G. and E.R. stained the tonsil biopsies, analyzed the results, and critically revised the manuscript. K.T. included the patients and critically revised the manuscript. H.U. supervised work in the laboratory and critically revised the manuscript. Å.B.A. designed the study and critically revised the manuscript. S.D.N. was principal investigator, designed the study, supervised data analysis, and critically revised the manuscript.

Received April 09, 2014

Accepted April 09, 2014

© 2014 by Lippincott Williams & Wilkins