Dataset Information

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-?B 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 TNF? production by B cells and/or T cells, accompanied by enhanced bone resorption and BMD loss. Reconstitution of TNF?- or RANKL-null T-cells and pharmacological TNF? 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.

SUBMITTER: Ofotokun I

PROVIDER: S-EPMC4580984 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ofotokun Ighovwerha I Titanji Kehmia K Vikulina Tatyana T Roser-Page Susanne S Yamaguchi Masayoshi M Zayzafoon Majd M Williams Ifor R IR Weitzmann M Neale MN

Nature communications 20150922

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 followi ...[more]

PMID: 26392000

Similar Datasets

Project description:To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue.Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen.Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-?) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers.The expression of the fibrosis-promoting molecule, TGF-?1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-?1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-?1, and interleukin-6.Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets