Metabolic determinants of HIV-1-associated pathogenesis

HIV-1相关发病机制的代谢决定因素

• 批准号: 405531809
• 负责人: Professor Dr. Marcus Altfeld
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/405531809?language=en
• 关键词: Metabolic; determinants; HIV; associated; pathogenesis

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.

尽管成功推出了抗逆转录病毒疗法，但 HIV-1 大流行仍导致了显着的发病率和死亡率，2021 年将出现 150 万新的 HIV-1 感染者，65 万人死于 HIV-1/艾滋病。此外，每年有超过 140 万感染 HIV-1 的母亲所生的婴儿接触 HIV-1，这会对这些接触 HIV-1 但未感染 (HEU) 的婴儿的免疫发育和生长产生长期影响。新兴的免疫代谢领域对宿主-病原体相互作用的代谢需求和代谢后果进行了全面评估，已开始对病毒引起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间的研究表明，HIV-1感染会引起免疫细胞早期和持续的代谢失调，而母亲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调查 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。我们建议进行综合研究来调查（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。这些高度综合的科学目标得到了非常成功的早期职业研究人员培训和职业发展战略的补充。准确了解调节病毒发病机制和抗病毒免疫的代谢途径将为代谢干预提供机会，以重建 HIV-1 感染者和 HEU 婴儿的免疫代谢稳态。