Immunometabolic Reprogramming via a Gut-derived Organoid Platform

Objective

Nearly 40 million people are living with HIV (PWH) worldwide. Although antiretroviral therapy suppresses viral replication, it does not eradicate HIV or prevent persistent gut pathology caused by infection. The gut-associated lymphoid tissue harbours most infected CD4 T cells and remains a site of chronic and systemic inflammation. This unresolved dysfunction drives premature ageing and multimorbidity in PWH, including cardiovascular disease, cancer, and frailty, representing a growing health burden in ageing HIV populations. Evidence shows that the metabolic state of immune cells determines both HIV persistence and intestinal barrier breakdown, making it an attractive therapeutic target. To exploit this, IRGOP will establish a first-in-kind organoid platform from patient gut biopsies combined with immune co-culture and HIV infection models to recreate gut pathology in vitro. This system will enable systematic screening of metabolic drugs, many already approved for other diseases, to identify candidates that restore barrier integrity and immune homeostasis. Advanced single-cell and spatial technologies will reveal mechanisms of action of hit compounds. By creating a translational pipeline from patient samples to therapeutic discovery, IRGOP will deliver mechanistic insight and repurposable drug candidates to reduce HIV-associated multimorbidity. Beyond HIV, the platform will remain a resource for tackling intestinal inflammation in other diseases. Ultimately, IRGOP aims to improve healthy life expectancy for PWH and reduce healthcare costs linked to chronic complications, while consolidating my trajectory towards research independence. Being hosted at the University of Copenhagen and Rigshospitalet, with access to the Novo Nordisk Foundation Initiative for Vaccines and Immunity (NIVI) organoid core and other advanced facilities, will provide world-class infrastructure and mentorship to maximise the project’s scientific, clinical and societal impact.