Restriction factors are cellular proteins that constitute one of the defence mechanisms developed by the host to fight viral infections. Friend virus susceptibility-1 (Fv1) is the prototypic restriction factor known for blocking murine leukemia virus (MLV) replication by targeting the viral capsid protein. This gene was found to be highly polymorphic between murine species as well as being under strong positive selection and having different restriction specificities. The origin of Fv1 remains unclear, however, its acquisition is known to have happened before the emergence of MLVs. It is, therefore, reasonable to speculate that non-MLV retroviruses have been involved in shaping Fv1 evolution.

The aim of this PhD project was to further understand how Fv1 evolves and interacts with retroviruses. A number of retroviruses from different genera were tested against a panel of Fv1s from different wild mice. Novel restriction activities were found for the gammaretroviruses Gibbon Ape Leukemia Virus and Feline Leukemia Virus as well as for two newly discovered endogenous retroviruses. More interestingly, the alpharetrovirus Rous Sarcoma Virus and the betaretrovirus Mouse Mammary Tumour Virus could be restricted by two Fv1s. These Fv1s showed no sign of gammaretrovirus restriction. Mapping studies pointed to the Fv1 C-terminal domain variable regions VA and VD as the interacting domains involved in these new specificities. Fine mapping revealed that single residue determinants were different for each virus. It was also shown that loss of activity is possible with very limited changes. To investigate the stage of the life cycle blocked for these viruses, qPCR assays were performed in Fv1 transduced cells to detect late reverse transcription and nuclear entry. The results confirmed that infection is blocked at the post-entry level after reverse transcription and before integration, as previously observed with MLV. Taken together with previous published data, these findings support the hypothesis that Fv1 is a very plastic system and that it might have evolved in response to non-gamma retroviruses from different genera that would have predated MLVs.