Bone resorbing osteoclasts form under the influence of the key osteoclastogenic cytokine Receptor activator of NF-κB ligand (RANKL), which is moderated by its physiological decoy receptor Osteoprotegerin (OPG). The immune system has a potent effect on both physiological and pathological bone turnover. Under basal conditions B-cells, secrete OPG and lymphocytes are thus protective of the skeleton. However, activated B- and T-cells can secrete RANKL leading to bone loss. HIV-infection causes dramatic disruptions of the immuno-skeletal interface, assaulting both T- and B-cell functions. Not surprisingly, bone loss has long been recognized in HIV-infection. Interestingly, regardless of regimen, antiretroviral therapy (ART) further exacerbates bone loss within the first 2 years of therapy. The net result is an up to 9-fold increase in the risk of bone fractures in HIV patients, a significant public health concern with high morbidity, mortality, and dramatic health care costs. The mechanisms by which HIV-infection and ART drive bone loss are however poorly defined. We recently reported bone loss in the HIV transgenic rat, an animal model of HIV-infection, as a result of diminished basal B-cell OPG production in favor of increased RANKL expression. This was compounded by an increased sensitivity of osteoclast precursors to RANKL. Importantly, in a recently published translational clinical study we validated this B-cell imbalance in OPG and RANKL production in HIV-infected ART-naïve patients and found that the B cell RANKL/OPG ratio was significantly inversely correlated with bone mineral density (BMD). However, the underlying mechanisms driving alterations in B-cell metabolism remain unknown. As IL-4 is a key regulator of humoral immunity, we examined IL-4 action on murine and human B-cells and found that IL-4 potently promotes B-cell production of OPG, but suppresses that of RANKL. In addition, IL-4 is known to decrease the sensitivity of osteoclast-precursors to RANKL. IL-4 knockout mice have a significant decline in BMD and an increase in bone resorption and a serum deficit in OPG concentrations. We propose to further define the mechanisms driving HIV- and ART-associated bone loss in two specific aims. Specific Aim 1 will quantify the role of IL-4 in the altered B-cell OPG and RANKL and enhanced bone resorption associated with ART-naïve HIV-infected subjects before and after ART initiation during and beyond the acute ART- induced bone loss period. Specific Aim 2 will employ state-of the-art animal models to define the sources and mechanistic functions of IL-4 in the maintenance of physiological bone mass by direct actions on osteoclasts and indirect actions though OPG.