Higher Levels of Osteoprotegerin and Immune Activation/Immunosenescence Markers Are Correlated with Concomitant Bone and Endovascular Damage in HIV-Suppressed Patients

Abstract

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. c-IMT and BMD in HIV infected subjects.

A. A higher c-IMT in HIV positive patients with a low BMD than in patients with a normal BMD was found. Horizontal bars represent the median. The upper and lower whisker indicate the third quartile +1.5 [Inter Quartile Range (IQR)] and first quartile -1.5(IQR). B. A linear regression analysis showed a negative correlation between c-IMT and BMD.

Fig 2. T cells phenotype in HIV infected subjects.

CD4+ and CD8+ immune activation (A, B) and immunesenescence (C, D) in HIV-infected subjects according to the presence of bone and vascular diseases: presence of two comorbidties (bone and endovascular damage), only one comorbidity (bone or endovascular damage), no comorbidity. Values are expressed as a percentage. The horizontal bars represent the median. The upper and lower whisker indicate the third quartile +1.5 [Inter Quartile Range (IQR)] and first quartile -1.5(IQR).

Fig 3. OPG plasma levels in HIV positive subjects.

OPG plasma levels (pmol/l) in HIV-infected subjects according to the presence of bone and endovascular damage: presence of two comorbidties (bone and endovascular damage), only one comorbidity (bone or endovascular damage), no comorbidity. The horizontal bars represent median. The upper and lower whisker indicate the third quartile +1.5 [Inter Quartile Range (IQR)] and first quartile -1.5(IQR).

Fig 4. ROC curve analysis.

The ROC curve area for CD8+CD28-CD57+ (AUC) was 0.79 and the cut-off >8.87% has a sensitivity of 75,61% (CI: 59.7% to 87.64%), specificity of 78.85% (CI: 65.30% to 88.94%) and a likelihood ratio of 3.57 (p<0.0001).