Effect of HIV Infection and Highly Active Antiretroviral Treatment (HAART) on Bone Homeostasis
Condition: HIV Infection; Osteopenia; Osteoporosis
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Osteoporosis; Bone Diseases, Metabolic
Study type: Observational

Summary: 
      Advances in HAART have been a huge success story in the management of HIV infection. However,
      serious metabolic complications including osteoporosis and bone fractures are increasingly
      been seen with HAART, and the responsible mechanisms remain poorly elucidated.

      The skeleton continually regenerates through homeostatic bone remodeling. Osteoclasts the
      cells responsible for bone resorption form under the influence of the key osteoclastogenic
      cytokine Receptor- Activator of NF-KB (RANKL). The osteoclastogenic and pro-resorptive
      activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG).
      Increase in the ratio of RANKL to OPG accelerates the rate of osteoclastic bone resorption
      leading to osteoporosis.

      The investigators' preliminary studies have now demonstrated that in an animal model of
      HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as
      observed in human patients. Furthermore, the investigators found that B cell expression of
      OPG is significantly downregulated, concurrent with a significant upregulation in production
      of RANKL.
    

Detailed description: 
      The investigators hypothesize that "immunological disruption of B cell number and/or
      function, may play a key causal role in the bone loss associated with HIV/AIDS, by driving a
      "switch" from OPG production to overproduction of RANKL". The investigators propose to
      determine the role of perturbations in B and T cells on OPG and RANKL production and on bone
      turnover.

      This is a cross-sectional analysis of changes in BMD (DXA), and B cell and T cell function in
      HIV seronegative/seropositive subjects matched by known risk factors for osteoporosis. Serum
      will be collected for quantitation of total OPG and RANKL, and for biochemical markers of
      bone turnover (CTx, and TRAP5b), specific and sensitive markers of osteoclast activity, and
      for osteocalcin and P1NP, specific and sensitive markers of bone formation by commercial
      ELISAs. Peripheral blood mononuclear cells (PBMC) will be isolated and total and percentage
      frequency and absolute number (/mL) of B cells (CD19+) and T cells (CD3) and their subsets
      (CD4 and CD8). B cells (CD19) and T cells (CD3 and CD4 and CD8) will be immunomagnetically
      purified and OPG and RANKL mRNA and protein production quantitated by RT-PCR and ELISA
      respectively. As a secondary endpoint, B cells will be fractionated into subsets based on
      differential expression of the markers CD10, CD21 and CD27 and OPG and RANKL production
      quantitated by in each subset by intracellular staining and FACS analysis.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy (HIV sero-negative) volunteers and otherwise healthy antiretroviral treatment naïve
        HIV-1 sero-positive patients, age >18 years.
      
Keywords: HIV; Osteopenia; Osteoporosis