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Graves’ disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4+ T-cell recovery

Sheikh, Virginiaa; Dersimonian, Rebeccab; Richterman, Aaron G.a; Porter, Brian O.a; Natarajan, Venc; Burbelo, Peter D.d; Rupert, Adamc; Santich, Brian H.a; Kardava, Lelaa; Mican, JoAnn M.a; Moir, Susana; Sereti, Irinia

doi: 10.1097/QAD.0000000000000006
Clinical Science

Objective: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4+ T-cell recovery, Graves’ disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear.

Design: Seven patients who developed Graves’ disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4+ T-cell count. Laboratory evaluations on stored cryopreserved samples were performed.

Methods: Immunophenotyping of peripheral blood mononuclear cells (PBMCs), T-cell receptor excision circle (TREC) analysis in PBMCs, measurement of serum cytokines, and luciferase immunoprecipitation systems (LIPS) analysis for autoimmune antibodies were performed on stored samples for cases and controls at baseline and longitudinally following ART initiation. TSH/thyrotropin receptor (TSH-R) antibody testing was performed on serum from cases. Data were analyzed using nonparametric testing.

Results: In comparison with controls, the proportion of naive CD4+ T cells increased significantly (P = 0.0027) in the Graves’ disease-IRD patients. TREC/106 PBMCs also increased significantly following ART in Graves’ disease-IRD patients compared with controls (P = 0.0071). Similarly, LIPS analysis demonstrated increases in nonthyroid-related autoantibody titers over time following ART in cases compared with controls.

Conclusion: Our data suggest that Graves’ disease-IRD, in contrast to early-onset IRD, is associated with naive and primary thymic emigrant CD4+ T-cell recovery and inappropriate autoantibody production.

aNational Institute of Allergy and Infectious Diseases (NIAID)

bBiostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

cScience Applications International Corporation-Frederick, Frederick National Laboratory, Frederick

dClinical Dental Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.

Correspondence to Virginia Sheikh, MD, MHS, National Institutes of Health, 10 Center Drive, Building 10, Room 8C408, Bethesda, MD 20892, USA. Tel: +1 301 435 7939; fax: +1 301 402 1137; e-mail:

Received 15 May, 2013

Revised 10 July, 2013

Accepted 11 July, 2013

This work was presented, in part, in abstract format at Keystone Symposium, HIV Immunobiology, March 2011.

© 2014 Lippincott Williams & Wilkins, Inc.