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Regulatory T Cells and the Risk of CMV End-Organ Disease in Patients With AIDS

Weinberg, Adriana MD*; Bosch, Ronald PhD; Bennett, Kara PhD; Tovar-Salazar, Adriana MS*; Benson, Constance A. MD; Collier, Ann C. MD§; Zolopa, Andrew MD; Gulick, Roy M. MD; Wohl, David MD#; Polsky, Bruce MD**; Erice, Alejo MD††; Jacobson, Mark A. MD‡‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2014 - Volume 66 - Issue 1 - p 25–32
doi: 10.1097/QAI.0000000000000095
Basic and Translational Science

Objectives: 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.

Design: 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 CD4+FOXP3+%, CD4+TNFα+%, and CD8+CD107a+% 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.

*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.

Correspondence to: Adriana Weinberg, MD, Department of Pediatric Medicine and Pathology, School of Medicine, University of Colorado Denver, 12700 E. 19th Avenue MS 8604, Aurora, CO 80045 724-4485 (e-mail: adriana.weinberg@ucdenver.edu).

Supported by the National Institutes of Health through the following grants: R21AI073121 (A.W.), AI 68636 and AI 38858 (ACTG), AI 68634 and AI 38855 (SDAC), AI-69419 (Cornell CTU), AI-51966 (RMG K-24), and AI 069434 (ACC).

Presented in part at the 18th Conference on Retroviruses and Opportunistic Infections, February 27 to March 3, 2011, Boston, MA.

The authors have no conflicts of interest to disclose.

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).

Received December 17, 2013

Accepted December 17, 2013

© 2014 by Lippincott Williams & Wilkins