Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss

• Type of Material: Article
• Authors: Ighoverha Ofotokun, Emory University; Kehmia Titanji, Emory University; Tatyana Vikulina, Emory University; Susanne Roser-Page, Atlanta Department of Veterans Affairs Medical Center; Masayoshi Yamaguchi, Emory University; Majd Zayzafoon, University of Alabama at Birmingham; Ifor Williams, Emory University; M. Neale Weitzmann, Emory University
• Language: English
• Date: 2015-09-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms9282
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 6
• Start Page: 8282
• End Page: 8282
• Grant/Funding Information: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under Award Number R01AR059364 and by the National Institute on Aging (NIA) under Award Number R01AG040013 to M.N.W. and I.O.; Histology services were performed by the University of Alabama at Birmingham, Center for Metabolic Bone Disease-Histomorphometry and Molecular Analysis Core Laboratory, supported by NIAMS (P30AR46031).; M.N.W. is also supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105) and by NIAMS grant (R01AR056090).; M.Z. is also supported by NIAMS grant (R01AR053898).
• Keywords: T cell; osteoclasts; Osteoporosis; bone loss; HIV; antiretroviral therapy; adoptive transfer
• Research Categories: Biology, Virology; Health Sciences, Immunology

Abstract

HIV infection causes bone loss. We previously reported that immunosuppression-mediated B-cell production of receptor activator of NF-κB ligand (RANKL) coupled with decline in osteoprotegerin correlate with decreased bone mineral density (BMD) in untreated HIV infection. Paradoxically, antiretroviral therapy (ART) worsens bone loss although existing data suggest that such loss is largely independent of specific antiretroviral regimen. This led us to hypothesize that skeletal deterioration following HIV disease reversal with ART may be related to T-cell repopulation and/or immune reconstitution. Here we transplant T cells into immunocompromised mice to mimic ART-induced T-cell expansion. T-cell reconstitution elicits RANKL and TNFα production by B cells and/or T cells, accompanied by enhanced bone resorption and BMD loss. Reconstitution of TNFα-or RANKL-null T-cells and pharmacological TNFα antagonist all protect cortical, but not trabecular bone, revealing complex effects of T-cell reconstitution on bone turnover. These findings suggest T-cell repopulation and/or immune reconstitution as putative mechanisms for bone loss following ART initiation.