title: Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss.
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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30303, USA.|Grady Healthcare System, Atlanta, Georgia 30303, USA.
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
authors.affiliation: Division of Endocrinology &Metabolism &Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Kehmia
authors.initials: K
authors.lastname: Titanji
authors.affiliation: Division of Endocrinology &Metabolism &Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Vikulina
authors.affiliation: Atlanta Department of Veterans Affairs Medical Center, Decatur, Georgia 30033, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roser-Page
authors.affiliation: Division of Endocrinology &Metabolism &Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35223, USA.
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30303, USA.
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.affiliation: Division of Endocrinology &Metabolism &Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Atlanta Department of Veterans Affairs Medical Center, Decatur, Georgia 30033, USA.
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D015519:Bone Density / Q000187:drug effects / Q000276:immunology; D001862:Bone Resorption; D018791:CD4 Lymphocyte Count; D005260:Female; D019674:Genes, T-Cell Receptor beta; D015497:HIV-1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010024:Osteoporosis / Q000139:chemically induced*; D013154:Spleen; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D014409:Tumor Necrosis Factor-alpha