Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion
Abstract 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 in...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02113-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544226891890688 |
|---|---|
| author | Jun Wang Nan Xiao Zhengnong Zhu Haiyan Qiao Fang Zhao Lukun Zhang Jizhou Gou Mengji Lu Yun He Hongzhou Lu Qian Li |
| author_facet | Jun Wang Nan Xiao Zhengnong Zhu Haiyan Qiao Fang Zhao Lukun Zhang Jizhou Gou Mengji Lu Yun He Hongzhou Lu Qian Li |
| author_sort | Jun Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-187b03defc9f430f8385cc8eb4b2bbfa |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-187b03defc9f430f8385cc8eb4b2bbfa2025-01-12T12:41:39ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111510.1038/s41392-024-02113-7Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansionJun Wang0Nan Xiao1Zhengnong Zhu2Haiyan Qiao3Fang Zhao4Lukun Zhang5Jizhou Gou6Mengji Lu7Yun He8Hongzhou Lu9Qian Li10National Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyDepartment of Pathology, Shenzhen Third People’s HospitalNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious Diseases, The Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41392-024-02113-7 |
| spellingShingle | Jun Wang Nan Xiao Zhengnong Zhu Haiyan Qiao Fang Zhao Lukun Zhang Jizhou Gou Mengji Lu Yun He Hongzhou Lu Qian Li Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion Signal Transduction and Targeted Therapy |
| title | Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion |
| title_full | Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion |
| title_fullStr | Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion |
| title_full_unstemmed | Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion |
| title_short | Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion |
| title_sort | comparing acute versus aids art initiation on hiv 1 integration sites and clonal expansion |
| url | https://doi.org/10.1038/s41392-024-02113-7 |
| work_keys_str_mv | AT junwang comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT nanxiao comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT zhengnongzhu comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT haiyanqiao comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT fangzhao comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT lukunzhang comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT jizhougou comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT mengjilu comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT yunhe comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT hongzhoulu comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion AT qianli comparingacuteversusaidsartinitiationonhiv1integrationsitesandclonalexpansion |