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.
Highlights
A decline in bone mineral density (BMD) of up to 6% is observed with antiretroviral therapy (ART) initiation, a loss comparable to that sustained during the early phase of menopause[19]
Emerging data suggest that direct HIV effects on the skeleton may be linked to altered immune function including activation of T cells[18] and significant B-cell dysfunction, with consequent increase in the receptor activator of NF-kB ligand (RANKL)/OPG ratio, favouring enhanced bone catabolism and loss of BMD16,17
We provide a ‘proof-of-concept’ that like HIV infection itself, the bone effect of ART may too have an immunocentric component driving bone loss though a mechanism aligned with immunologic events associated with HIV disease reversal and immune reconstitution and/or reactivation that may lead to persistent low-level chronic inflammation
Summary
Antiretroviral therapy (ART) worsens bone loss 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. ART drug classes with distinct modes of action mediated through different biochemical pathways are all associated with bone loss[26,27,28], suggesting that bone loss is independent of antiretroviral regimen[26,29] and implying an indirect effect of ART on bone homeostasis One such indirect action may be related to HIV disease reversal and homeostatic expansion of the immune cells. We further demonstrated that bone loss associated with disruption of the immuno-skeletal interface could be fully prevented by anti-resorptive medication prophylaxis using zoledronic acid in T-cell-reconstituted animals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
