Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells
We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated v...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/18447 |
| _version_ | 1811235876410228736 |
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| author | Erik C Hansen Monica Ransom Jay R Hesselberth Nina N Hosmane Adam A Capoferri Katherine M Bruner Ross A Pollack Hao Zhang Michael Bradley Drummond Janet M Siliciano Robert Siliciano James T Stivers |
| author_facet | Erik C Hansen Monica Ransom Jay R Hesselberth Nina N Hosmane Adam A Capoferri Katherine M Bruner Ross A Pollack Hao Zhang Michael Bradley Drummond Janet M Siliciano Robert Siliciano James T Stivers |
| author_sort | Erik C Hansen |
| collection | DOAJ |
| description | We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection. |
| first_indexed | 2024-04-12T11:59:37Z |
| format | Article |
| id | doaj.art-db3a368d8fbf4bbfb556874b4bc89f4b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T11:59:37Z |
| publishDate | 2016-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-db3a368d8fbf4bbfb556874b4bc89f4b2022-12-22T03:33:53ZengeLife Sciences Publications LtdeLife2050-084X2016-09-01510.7554/eLife.18447Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cellsErik C Hansen0Monica Ransom1Jay R Hesselberth2Nina N Hosmane3Adam A Capoferri4Katherine M Bruner5Ross A Pollack6Hao Zhang7Michael Bradley Drummond8Janet M Siliciano9Robert Siliciano10James T Stivers11https://orcid.org/0000-0003-2572-7807Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United StatesDepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United StatesW Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, United StatesDepartment of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United StatesWe report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection.https://elifesciences.org/articles/18447U/A DNA base pairs in HIVuracil base excision repairlatency in macrophagesviral restriction |
| spellingShingle | Erik C Hansen Monica Ransom Jay R Hesselberth Nina N Hosmane Adam A Capoferri Katherine M Bruner Ross A Pollack Hao Zhang Michael Bradley Drummond Janet M Siliciano Robert Siliciano James T Stivers Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells eLife U/A DNA base pairs in HIV uracil base excision repair latency in macrophages viral restriction |
| title | Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells |
| title_full | Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells |
| title_fullStr | Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells |
| title_full_unstemmed | Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells |
| title_short | Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells |
| title_sort | diverse fates of uracilated hiv 1 dna during infection of myeloid lineage cells |
| topic | U/A DNA base pairs in HIV uracil base excision repair latency in macrophages viral restriction |
| url | https://elifesciences.org/articles/18447 |
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