Metabolic determinants of HIV-1-associated pathogenesis

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Despite the successful roll-out of antiretroviral therapy, significant morbidity and mortality is caused by the HIV-1 pandemic, with 1.5 million new HIV-1 infections occurring in 2021, and 650,000 individuals dying of HIV-1/AIDS. Furthermore, exposure to HIV-1 in the over 1.4 million infants born to HIV-1-infected mothers annually has long-term consequences for immune development and growth in these HIV-1-exposed but uninfected (HEU) infants. The newly emerging field of immune-metabolism, which provides a comprehensive assessment of the metabolic requirements for and metabolic consequence of host-pathogen interactions, has started to give new insights into the mechanisms by which virus-induced dysregulation of metabolic pathways contributes to HIV-1-associated morbidity and mortality. Studies by the applicants during the first funding period have shown that HIV-1 infection induces early and persistent metabolic dysregulations in immune cells, and that metabolic dysregulations resulting from maternal HIV-1 infection are associated with decreased growth and immunity in HEU infants. The overall goal of this African-German research network is to investigate the determinants of pathogenesis in HIV-1-infected individuals and HEU children, with particular focus on the metabolic factors that lead to HIV-1-associated pathology. We propose integrated studies to investigate (i) the impact of HIV-1 virulence on cell metabolism, (ii) the consequences of metabolic dysregulation on immune function, and (iii) the impact of maternal HIV-1 and cART-mediated metabolic dysregulations on immune development of HEU children. These highly-integrated scientific objectives are complemented by a very successful early-career researcher training and career development strategy. A precise understanding of the metabolic pathways regulating viral pathogenesis and antiviral immunity will provide the opportunity for metabolic interventions to reconstitute immune-metabolic homeostasis in HIV-1-infected individuals and HEU infants.