HIV infection and its therapy are associated with disturbances in bone remodeling resulting in low bone mineral density (BMD). Bone remodeling is controlled within the bone microenvironment by interactions between T lymphocyte- and osteoblast-derived cytokines, specifically receptor activator of nuclear factor kappaB ligand (RANKL) and its decoy receptor osteoprotegerin. Although the mechanism of HIV-associated bone loss is not understood, we hypothesize that it results from disturbances in the regulation of osteoclastogenesis. We have demonstrated significantly greater osteoclast differentiation in peripheral blood mononuclear cells (PBMC) from HIV+ patients than HIV- controls. Moreover, we have observed significantly increased osteoclast activity in vitro utilizing PBMCs and sera from HIV+ patients treated with highly active antiretroviral therapies (HAART) that incorporate protease inhibitors (PI) that interfere with RANKL signaling compared to HAART regimens incorporating PIs that do not have this effect. We hypothesize that bone resorption is initiated in HIV infection by the synergistic influence on osteoclast precursors of two cytokines upregulated during the T cell activation characteristic of both anti-retroviral treatment of HIV and T cell exposure to HIV envelope gp120: RANKL and tumor necrosis factor (TNF)-alpha. We further hypothesize that this bone resorption may be accelerated by PIs which can abrogate at least one of two physiologic, interferon (IFN)-linked blocks to RANKL; activity. We will test these hypotheses using: (1) in vitro models for osteoclast differentiation and RANKL-driven signaling in peripheral blood and bone-derived precursors, as modified by HIV and anti-HIV PIs; and (2) cross-sectional and longitudinal analyses of HIV- and HIV+ postmenopausal women, the latter treatment-naive and on various HAART regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065511-04
Application #
7347520
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Malozowski, Saul N
Project Start
2005-02-01
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$320,023
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065