Lymphocyte Activation and Bone Turnover in HIV-Infected Young Adults; A Sub-Study of Adolescent Medicine Trials Network Protocol 061

Rationale: HIV infection is associated with chronic inflammation contributing to long-term skeletal complications and bone loss. Cause of bone turnover in HIV-infected patients is unknown. We hypothesized that biomarkers of lymphocyte activation are associated with biomarkers of bone turnover in HIV-infected youth.

Methods: Young adults were selected for exploratory evaluation (n=16, median age 21 years, 88% male) from those who enrolled in a prospective study of antiretroviral therapy (ART) prior to CD4 T-cell attrition. Studies were performed using cryopreserved cells and sera obtained prior to and at 24 or 48 weeks post ART initiation. Biomarkers of bone turnover, lymphocyte and macrophage activation were assayed using 13 plex Luminex assay or multi-parameter flow cytometry. A Spearman’s rank correlation (r_s) was used to assess associations between biomarkers.

Results: The only association between bone turnover and macrophage activation was a negative correlation of soluble CD163 with ACTH following ART initiation (r_s=-0.62, p=0.01). The largest correlations were seen in measures of lymphocyte activation measured by soluble CD27, which correlated with adiponectin levels prior to ART (r_s=0.54, p=0.04), and expression of lymphocyte activation markers on CD8 Central Memory T-cells. Increased levels of CD28 expression and declines in CD38 and HLA DR expression correlated with increased levels of C-terminal telopeptide (r_s=0.57, r_s=-0.50, and r_s=-0.61, respectively; p<0.05). Similar associations were seen with levels of receptor activator of NFκB ligand and osteopontin.

Conclusions: Bone turnover was more often associated with lymphocyte rather than macrophage activation. ART targets activated lymphocytes and its introduction may be beneficial in preventing early bone turnover.