Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration
<p>Abstract</p> <p>Background</p> <p>The development of an immunocompetent, genetically modified mouse model to study HIV-1 pathogenesis and to test antiviral strategies has been hampered by the fact that cells from native mice do not or only inefficiently support sever...
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| Format: | Article |
| Language: | English |
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BMC
2008-07-01
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| Series: | Retrovirology |
| Online Access: | http://www.retrovirology.com/content/5/1/58 |
| _version_ | 1811249078129917952 |
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| author | Goffinet Christine Tervo Hanna-Mari Keppler Oliver T |
| author_facet | Goffinet Christine Tervo Hanna-Mari Keppler Oliver T |
| author_sort | Goffinet Christine |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The development of an immunocompetent, genetically modified mouse model to study HIV-1 pathogenesis and to test antiviral strategies has been hampered by the fact that cells from native mice do not or only inefficiently support several steps of the HIV-1 replication cycle. Upon HIV-1 infection, mouse T-cell lines fail to express viral proteins, but the underlying replication barrier has thus far not been unambiguously identified. Here, we performed a kinetic and quantitative assessment of consecutive steps in the early phase of the HIV-1 replication cycle in T-cells from mice and humans.</p> <p>Results</p> <p>Both T-cell lines and primary T-cells from mice harbor a severe post-entry defect that is independent of potential species-specTR transactivation. Reverse transcription occurred efficiently following VSV-G-mediated entry of virions into mouse T-cells, and abundant levels of 2-LTR circles indicated successful nuclear import of the pre-integration complex. To probe the next step in the retroviral replication cycle, i.e. the integration of HIV-1 into the host cell genome, we established and validated a nested real-time PCR to specifically quantify HIV-1 integrants exploiting highly repetitive mouse <it>B1 </it>elements. Importantly, we demonstrate that the frequency of integrant formation is diminished 18- to > 305-fold in mouse T-cell lines compared to a human counterpart, resulting in a largely abortive infection. Moreover, differences in transgene expression from residual vector integrants, the transcription off which is cyclin T1-independent, provided evidence for an additional, peri-integrational deficit in certain mouse T-cell lines.</p> <p>Conclusion</p> <p>In contrast to earlier reports, we find that mouse T-cells efficiently support early replication steps up to and including nuclear import, but restrict HIV-1 at the level of chromosomal integration.</p> |
| first_indexed | 2024-04-12T15:39:03Z |
| format | Article |
| id | doaj.art-9b10c627d4eb4ba0bd5c66580cdd97a1 |
| institution | Directory Open Access Journal |
| issn | 1742-4690 |
| language | English |
| last_indexed | 2024-04-12T15:39:03Z |
| publishDate | 2008-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Retrovirology |
| spelling | doaj.art-9b10c627d4eb4ba0bd5c66580cdd97a12022-12-22T03:26:51ZengBMCRetrovirology1742-46902008-07-01515810.1186/1742-4690-5-58Mouse T-cells restrict replication of human immunodeficiency virus at the level of integrationGoffinet ChristineTervo Hanna-MariKeppler Oliver T<p>Abstract</p> <p>Background</p> <p>The development of an immunocompetent, genetically modified mouse model to study HIV-1 pathogenesis and to test antiviral strategies has been hampered by the fact that cells from native mice do not or only inefficiently support several steps of the HIV-1 replication cycle. Upon HIV-1 infection, mouse T-cell lines fail to express viral proteins, but the underlying replication barrier has thus far not been unambiguously identified. Here, we performed a kinetic and quantitative assessment of consecutive steps in the early phase of the HIV-1 replication cycle in T-cells from mice and humans.</p> <p>Results</p> <p>Both T-cell lines and primary T-cells from mice harbor a severe post-entry defect that is independent of potential species-specTR transactivation. Reverse transcription occurred efficiently following VSV-G-mediated entry of virions into mouse T-cells, and abundant levels of 2-LTR circles indicated successful nuclear import of the pre-integration complex. To probe the next step in the retroviral replication cycle, i.e. the integration of HIV-1 into the host cell genome, we established and validated a nested real-time PCR to specifically quantify HIV-1 integrants exploiting highly repetitive mouse <it>B1 </it>elements. Importantly, we demonstrate that the frequency of integrant formation is diminished 18- to > 305-fold in mouse T-cell lines compared to a human counterpart, resulting in a largely abortive infection. Moreover, differences in transgene expression from residual vector integrants, the transcription off which is cyclin T1-independent, provided evidence for an additional, peri-integrational deficit in certain mouse T-cell lines.</p> <p>Conclusion</p> <p>In contrast to earlier reports, we find that mouse T-cells efficiently support early replication steps up to and including nuclear import, but restrict HIV-1 at the level of chromosomal integration.</p>http://www.retrovirology.com/content/5/1/58 |
| spellingShingle | Goffinet Christine Tervo Hanna-Mari Keppler Oliver T Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration Retrovirology |
| title | Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration |
| title_full | Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration |
| title_fullStr | Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration |
| title_full_unstemmed | Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration |
| title_short | Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration |
| title_sort | mouse t cells restrict replication of human immunodeficiency virus at the level of integration |
| url | http://www.retrovirology.com/content/5/1/58 |
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