Project Summary / Abstract The development of highly effective antiretroviral (ARV) therapies has significantly increased the lifespan of people living with HIV (PLWH). Yet as HIV has become a chronic disease, it is becoming increasingly clear that PLWH have an increased risk for and an earlier onset of a variety of comorbidities, including osteoporosis. Our long-term goal is to identify the mechanism(s) of HIV and ARV-mediated bone loss. While human studies are highly valuable in defining phenomena and associations, they are complicated by sample accessibility, numerous confounding variables, and limitations in assessing cause and effect. Small animal models can be of value to probe the mechanism(s) implicated in HIV/ARV-induced bone loss. However, a critical barrier in the field is the difficulty in modeling HIV infection and ARV treatment in small animal models. Although several rodent models have been used to study the effects of HIV on bone, each has its own unique limitations. Therefore, in the current proposal we aim to characterize the NSG-HuPBMC mouse model to study the effects of HIV infection and ARV treatment on bone. The model has several key advantages: (1) it is relatively cost effective and less complex than other models, (2) allows for reconstitution and infection of cells of interest, and (3) there is no irradiation or fetal tissue required. The proposal will test the hypothesis that both HIV infection and ARV treatment induce loss of bone mass and reduced bone quality and strength in NSG-HuPBMC mice via two separate but independent aims that will determine the effects of HIV infection (Aim 1) and ARV treatment alone and in combination with HIV infection (Aim 2) on bone. The research proposal is well suited as a high risk/ high reward R21 application because assessing bone loss in this model can potentially establish it as a suitable model for studying HIV skeletal co-morbidities and most importantly define mechanisms that may inform the human condition.