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Interferon inhibits transformation by murine sarcoma viruses before integration of provirus
Abstract:
Neoplastic transformation by C-type retroviruses requires synthesis of a DNA copy (the provirus) of the RNA genome and its integration into the host cell DNA. We have previously shown that interferon (IFN) can stably prevent transformation of murine fibroblasts by the Kirsten strain of murine sarcoma virus (KiMSV), a murine leukaemia virus (MLV). A series of cell clones (IFN clones), isolated in the presence of IFN (10(4) U ml-1) from cultures of NIH-3T3 cells which had been treated with IFN, and then infected with KiMSV (KiMLV) in conditions where every cell was infected, were shown to be phenotypically untransformed. These untransformed cells did not produce virus or contain rescuable KiMSV. However, cells isolated using an identical procedure, but in the absence of IFN, were uniformly transformed and all produced KiMSV (KiMLV) or contained rescuable KiMSV. It was concluded that IFN either prevents synthesis or integration of the provirus, or else that in the presence of IFN the provirus is integrated such that it is not expressed. We now show that five representative clones contain no detectable KiMSV proviral DNA, and also that the initial stages of infection by KiMSV (KiMLV) are inhibited by IFN treatment. IFN seems to act before integration, preventing either the synthesis or the integration of proviral DNA.
Insights
Interferon (IFN) prevents cancer-causing retrovirus transformation by blocking proviral DNA synthesis or integration. This antiviral action occurs early in infection, before provirus insertion into host cell DNA.
Area of Science:
- Virology
- Molecular Biology
- Cancer Research
Background:
- C-type retroviruses cause neoplastic transformation through proviral DNA integration.
- Interferon (IFN) has been shown to prevent transformation by Kirsten strain of murine sarcoma virus (KiMSV).
Purpose of the Study:
- To investigate the mechanism by which IFN prevents retroviral transformation.
- To determine if IFN inhibits proviral DNA synthesis or integration.
Main Methods:
- Isolation of IFN-treated and untreated murine fibroblast clones after KiMSV infection.
- Phenotypic analysis of transformed and untransformed cell clones.
- Detection of KiMSV proviral DNA in cell clones.
Main Results:
- IFN-treated clones remained untransformed, lacked viral production, and contained no detectable KiMSV proviral DNA.
- Untreated clones were transformed and produced infectious KiMSV.
- IFN treatment inhibited early stages of KiMSV infection.
Conclusions:
- IFN prevents retroviral transformation by inhibiting proviral DNA synthesis or integration.
- IFN acts at a pre-integration step, blocking the formation or insertion of proviral DNA.
- IFN is a potent inhibitor of retroviral infection and transformation.