Bone and fat cross-talk in antiretroviral therapy (ART) treated HIV patients

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Project Summary / Abstract The widespread use of combination antiretroviral therapy (cART) has significantly increased the lifespan of people living with HIV (PLWH). As HIV has become a chronic disease, there is a growing concern of the disproportionate risk of a variety of comorbidities. Two such comorbidities that occur at a higher prevalence in cART treated PLWH include bone loss and fat gain. Interestingly, as new treatment recommendations have shifted to cART regimens that are less bone toxic, there appears to be an increased prevalence of excessive fat gain and an increased risk for the development of metabolic syndrome. Our long-term goal is to determine the mechanisms contributing to these comorbid conditions in cART treated PLWH in order to find less deleterious treatment options. The current proposal will test the central hypothesis that the hormonal communication between bone and fat explains how antiretrovirals (ARVs) contribute to bone loss and fat gain in PLWH. Our hypothesis is based on our preliminary data showing hormonal changes in response to ARVs and correlations between the changes in bone and fat hormones and BMD loss and fat gain with cART initiation. To test our hypothesis, we propose to take a hierarchical approach that will include in vitro, preclinical, and human subject studies. In Aim 1, we will define the contribution of individual ARVs and cART to bone and fat cellular function and hormonal production using primary human cells. In Aim 2, we will investigate the skeletal and metabolic response to individual ARVs and cART using both an uninfected wild-type mouse and a humanized mouse model of HIV-infection. Finally, in Aim 3, we will determine the association between bone and fat-derived hormones and bone mass and body composition in three critical treatment stages, cART initiation, long-term stable cART treatment, and switching cART regimens. If successful, this proposal, submitted by an early stage investigator (ESI), will provide significant insights into key comorbidities faced by HIV patients on cART—specifically by illuminating how individual ARVs negatively affect bone/fat cell function and hormonal production. At the same time, this proposal will increase our general understanding of the bone- fat hormonal axis.