Early antiretroviral therapy(ART)initiation is known to limit the establishment of the HIV reservoir,with studies suggesting benefits such as a reduced number of infected cells and a smaller latent reservoir.However,t...Early antiretroviral therapy(ART)initiation is known to limit the establishment of the HIV reservoir,with studies suggesting benefits such as a reduced number of infected cells and a smaller latent reservoir.However,the long-term impact of early ART initiation on the dynamics of the infected cell pool remains unclear,and clinical evidence directly comparing proviral integration site counts between early and late ART initiation is limited.In this study,we used Linear Target Amplification-PCR(LTA-PCR)and Next Generation Sequencing to compare unique integration site(UIS)clonal counts between individuals who initiated ART during acute HIV infection stage(Acute-ART group)and those in the AIDS stage(AIDS-ART group).Our analysis revealed distinct clonal distribution patterns,with greater UIS heterogeneity in Acute-ART group and more homogeneity in AIDS-ART group.Monoclonal UIS accumulation,predominantly in-gene regions,was influenced by ART timing and duration,with early treatment delaying this process.Host cell genes integrated by HIV provirus as monoclonal types were enriched in cell cycle and lymphocyte activation pathways.Tumor suppressor genes(TSGs)were more frequently integrated as monoclonal types in AIDS-ART group,suggesting potential risk factors.Overall,we introduced a sequencing method to assess provirus size in human peripheral blood and identified the widespread presence of monoclonal distribution of UIS in AIDS-ART group after long-term treatment.The early intervention helps slow the progress of clonal expansion of infected cells,reducing the formation of stable and persistent reservoirs,and ultimately posing fewer barriers to achieving a functional cure.展开更多
基金supported by the China’s National Key R&D Programs(No.2023YFC2306700)National Science Foundation of China(No.82301973)+11 种基金the Chinesisch-Deutsches Mobilitats programm(No.M-0569)Basic and Applied Basic Research Fund of Guangdong Province:Regional Joint Fund-Youth Fund Project(No.2021A1515110831No.2022 A1515111163)the China Post-Doctoral Science Foundation(No.2022M721473)the Shenzhen Third People’s Hospital project(No.21250G1001No.22240G1005No.XKJS-CRGRK-008)Shenzhen Science and Technology Innovations Committee(No.JSGGZD20220822095200001,No.JCYJ20220530163406014)the Top Talent Support Program for young and middle-aged people of Wuxi Health Committee(No.BJ2023093)Research Projects of Wuxi Health Committee(No.M202203)the Wuxi Science and Technology Fund Project(No.Y20222008)We also extend our gratitude to Daniel Hoffmann from the Department of Bioinformatics and Computational Biophysics,University of Duisburg-Essen,Essen 45147,Germany,for his invaluable guidance in bioinformatic analysis.
文摘Early antiretroviral therapy(ART)initiation is known to limit the establishment of the HIV reservoir,with studies suggesting benefits such as a reduced number of infected cells and a smaller latent reservoir.However,the long-term impact of early ART initiation on the dynamics of the infected cell pool remains unclear,and clinical evidence directly comparing proviral integration site counts between early and late ART initiation is limited.In this study,we used Linear Target Amplification-PCR(LTA-PCR)and Next Generation Sequencing to compare unique integration site(UIS)clonal counts between individuals who initiated ART during acute HIV infection stage(Acute-ART group)and those in the AIDS stage(AIDS-ART group).Our analysis revealed distinct clonal distribution patterns,with greater UIS heterogeneity in Acute-ART group and more homogeneity in AIDS-ART group.Monoclonal UIS accumulation,predominantly in-gene regions,was influenced by ART timing and duration,with early treatment delaying this process.Host cell genes integrated by HIV provirus as monoclonal types were enriched in cell cycle and lymphocyte activation pathways.Tumor suppressor genes(TSGs)were more frequently integrated as monoclonal types in AIDS-ART group,suggesting potential risk factors.Overall,we introduced a sequencing method to assess provirus size in human peripheral blood and identified the widespread presence of monoclonal distribution of UIS in AIDS-ART group after long-term treatment.The early intervention helps slow the progress of clonal expansion of infected cells,reducing the formation of stable and persistent reservoirs,and ultimately posing fewer barriers to achieving a functional cure.
