Flux Balance Analysis Reveals Potential Anti-HIV-1 Metabolic Targets  

作　　者：Runpeng Han Fei Luo Haisheng Yu Yajun Yan Yan Gong Conghua Xie Liang Cheng 

机构地区：[1]Department of Radiation and Medical Oncology,Medical Research Institute,Zhongnan Hospital of Wuhan University,Wuhan University,Wuhan 430071,China [2]Frontier Science Center for Immunology and Metabolism,Zhongnan Hospital of Wuhan University,State Key Laboratory of Virology,Wuhan University,Wuhan 430071,China [3]Guangzhou Eighth People's Hospital,Guangzhou Medical University,Guangzhou 510440,China [4]Department of Infectious Diseases,Zhongnan Hospital of Wuhan University,Wuhan 430071,China [5]Department of Biological Repositories,Zhongnan Hospital of Wuhan University,Wuhan 430071,China [6]Wuhan Research Center for Infectious Diseases and Cancer,Chinese Academy of Medical Sciences,Wuhan 430071,China

出　　处：《Infectious Diseases & Immunity》2024年第2期61-68,共8页感染性疾病与免疫（英文）

基　　金：the National Natural Science Foundation of China(82071784);the Fundamental Research Funds for the Central Universities(2042022dx0003 and PTPP2023002);the Key Research and Development Project of Hubei Province(2020BCA069);the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(ZNJC202007).

摘　　要：Background:Human immunodeficiency virus type 1(HIV-1)remains a persistent global health challenge.Therefore,a continuous exploration of novel therapeutic strategies is essential.A comprehensive understanding of how HIV-1 utilizes the cellular metabolism machinery for replication can provide insights into new therapeutic approaches.Methods:In this study,we performed a flux balance analysis using a genome-scale metabolic model(GEM)integrated with an HIV-1 viral biomass objective function to identify potential targets for anti–HIV-1 interventions.We generated a GEM by integrating an HIV-1 production reaction into CD4+T cells and optimized for both host and virus optimal states as objective functions to depict metabolic profiles of cells in the status for optimal host biomass maintenance or for optimal HIV-1 virion production.Differential analysis was used to predict biochemical reactions altered optimal for HIV-1 production.In addition,we conducted in silico simulations involving gene and reaction knock-outs to identify potential anti–HIV-1 targets,which were subsequently validated by human phytohemagglutinin(PHA)blasts infected with HIV-1.Results:Differential analysis identified several altered biochemical reactions,including increased lysine uptake and oxidative phosphorylation(OXPHOS)activities in the virus optima compared with the host optima.In silico gene and reaction knock-out simulations revealed de novo pyrimidine synthesis,and OXPHOS could serve as potential anti–HIV-1 metabolic targets.In vitro assay confirmed that targeting OXPHOS using metformin could suppress the replication of HIV-1 by 56.6%(385.4±67.5 pg/mL in the metformintreated group vs.888.4±32.3 pg/mL in the control group,P<0.001).Conclusion:Our integrated host-virus genome-scale metabolic study provides insights on potential targets(OXPHOS)for anti-HIV therapies.

关 键 词：HIV-1 Flux balance analysis Genome-scale metabolic models Viral biomass objective function Therapeutic target 

分 类 号：R512.91[医药卫生—内科学]