Metabolic determinants of HIV-1-associated pathogenesis

尽管成功推出了抗逆转录病毒疗法，但艾滋病毒-1大流行病造成了大量发病率和死亡率，2021年有150万新的艾滋病毒-1感染病例，65万人死于艾滋病毒-1/艾滋病。此外，每年感染艾滋病毒1的母亲所生的140多万婴儿暴露于艾滋病毒1，对这些暴露于艾滋病毒1但未感染（HEU）的婴儿的免疫发育和生长产生长期影响。新出现的免疫代谢领域提供了对宿主-病原体相互作用的代谢需求和代谢后果的全面评估，已经开始对病毒诱导的代谢途径失调导致hiv -1相关发病率和死亡率的机制提供新的见解。申请人在第一个资助期的研究表明，HIV-1感染诱导免疫细胞早期和持续的代谢失调，母体HIV-1感染引起的代谢失调与HEU婴儿的生长和免疫力下降有关。这个非洲-德国研究网络的总体目标是研究hiv -1感染者和HEU儿童发病机制的决定因素，特别关注导致hiv -1相关病理的代谢因素。我们建议综合研究(i) HIV-1毒力对细胞代谢的影响，（ii）代谢失调对免疫功能的影响，以及（iii）母亲HIV-1和cart介导的代谢失调对HEU儿童免疫发育的影响。这些高度整合的科学目标与非常成功的早期职业研究人员培训和职业发展战略相辅相成。对调节病毒发病机制和抗病毒免疫的代谢途径的精确理解将为代谢干预提供机会，以重建hiv -1感染个体和HEU婴儿的免疫代谢稳态。

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.