PROJECT SUMMARY/ABSTRACT People with human immunodeficiency virus (HIV), (PWH), are at increased risk of frailty, which increases the risk of adverse age-related outcomes, including falls, hospitalization and mortality. The mechanisms of frailty are not completely understood, particularly among PWH. The objective of this proposal is to study the extent to which sex hormone binging globulin (SHBG) post-modification is associated with frailty and inflammation in men with HIV. We hypothesize that SHBG are key biomarkers for identifying PWH at the highest risk of frailty and who may benefit from intervention with anabolic agents. Therefore, pro-inflammatory glycans on SHBG will be higher among frail compared to non-frail men with HIV and with higher SHBG concentrations. Our specific aim is to determine the association of novel SHBG glycans with frailty among men with HIV. In Aim 3, we will study novel SHBG glycoforms in men with HIV, the identification and quantification of SHBG glycoforms will be performed by new proposed advanced biochemical techniques, including SHBG immunoprecipitation optimization, glycoproteomics with digestion, and liquid chromatography-mass spectrometry (LCMS/MS). The proposed research aims to provide new insights to the contribution of free testosterone and SHBG in frailty and its relationship with systemic inflammation. The goals during the award period include gaining advanced expertise in biostatistical methods, design and conduct epidemiological studies, as well as hands-on experience in the measurement of glycoforms from plasma proteins and interpretation of glycomic data through mentored research, tailored didactic coursework, and supervised performance of relevant laboratory techniques. Long-term goals include developing a career as an independent investigator in translational epidemiology and developing new approaches to treating and preventing age-related outcomes such as frailty in PWH.