Defining cellular and molecular signatures of inflammation in people with suppressed HIV that promote chronic kidney disease

About This Grant

ABSTRACT People with HIV-1 (PWH) on antiretroviral therapy (ART) are prone to experiencing chronic inflammation despite effective viral suppression. This sustained inflammation has been linked to an elevated risk of developing a variety of age-associated comorbidities, including chronic kidney disease (CKD). Preliminary data supporting this study demonstrates multiple distinct inflammatory endotypes among aging PWH on ART, several defined by levels of chemokine C-C motif ligand 2 (CCL2), a critical mediator and biomarker of kidney injury and disease. However, the precise cellular and molecular inflammatory immune endotypes in PWH that could lead to disease remain undefined. Moreover, how endotypes defined by circulating inflammatory markers impact organ- compartmentalized inflammation and the functional and molecular states of immune cells are unknown. The overall objective of this project is to define the early cellular and molecular signatures of inflammation associated with the progressive development of CKD in PWH on ART in both blood and urine. This will be achieved by comprehensively defining plasma inflammatory endotypes in a retrospective cohort of aging (50+ years) PWH on ART, sampled as they progressed from early to later stage kidney disease, with comparison to PWH on ART with normal renal function. In addition, systems immunology will be used to characterize the soluble and cellular inflammatory profiles of peripheral blood and urine in a prospective cohort of 200 aging PWH on ART. Urine, a readily accessible non-invasive biofluid, contains proteins and viable cells originating from the kidney that can serve as indicators of renal inflammation and overall kidney function. A combination of advanced machine learning approaches, clinical tests, and human kidneys-on-chips models will be applied to define the relationship between systemic, urinary, and renal cell inflammation and dysfunction in PWH on ART that are associated with onset of CKD. This project will test the hypothesis that specific inflammatory immune endotypes can be identified in PWH on ART that promote the activation and dysregulation of immune and kidney cells, contributing to the development of CKD. The hypothesis will be tested, and the overall objective achieved, with completion of three Specific Aims. Aim 1 will define plasma inflammatory endotypes of aging PWH on ART and identify signatures that predict CKD. Aim 2 will identify how plasma inflammatory endotypes impact the cellular, metabolic, and functional programs in blood and urine of aging PWH on ART. Finally, Aim 3 will determine the mechanisms of activation of renal inflammatory programs using kidneys-on-chips. This research will identify specific endotypes of inflammation associated with development pf CKD and uncover pathways driving chronic inflammation in the blood and urine that promote kidney injury and disease. This knowledge will enable the development of CKD risk prediction tools and of therapeutic interventions like CCL2 signaling inhibitors to reduce inflammation-related kidney disease and other comorbidities in this expanding population.