Mouse T-cells restrict replication of human immunodeficiency virus at the level of integration
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.
Results: Both T-cell lines and primary T-cells from mice harbor a severe post-entry defect that is independent of potential species-specific differences in LTR 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 B1 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.
Conclusions: 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.
Author: Hanna-Mari Tervo, Christine Goffinet and Oliver T Keppler
Credits/Source: Retrovirology 2008, 5:58
Published on: 2008-07-08
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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