The extent of virus transmission among individuals and species is generally determined by the presence of specific membraneembedded virus receptors required for virus entry. Interaction of the viral envelope glycoprotein (Env) with a specific cellular receptor is the first and crucial step in determining host specificity. Using a well-established retroviral model-Avian Rous sarcoma virus (RSV)-we analyzed changes in an RSV variant that had repeatedly been able to infect rodents. By envelope gene (env) sequencing, we identified eight mutations that do not match the already described mutations influencing the host range. Two of these mutations-one at the beginning (D32G) of the surface Env subunit (SU) and the other at the end of the fusion peptide region (L378S)-were found to be of critical importance, ensuring transmission to rodent, human, and chicken cells lacking the appropriate receptor. Furthermore, we carried out assays to examine the virus entry mechanism and concluded that these two mutations cause conformational changes in the Env variant and that these changes lead to an activated, or primed, state of Env (normally induced after Env interaction with the receptor). In summary, our results indicate that retroviral host range extension is caused by spontaneous Env activation, which circumvents the need for original cell receptor. This activation is, in turn, caused by mutations in various env regions.
Lounková, A., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic; Koslaa, J., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic; Přikryl, D., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic; Štafl, K., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic; Kǔcerová, D., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic; Svoboda, J., Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic
Recommended Citation:
Lounková A.,Koslaa J.,Přikryl D.,et al. Retroviral host range extension is coupled with Env-Activating mutations resulting in receptor-independent entry[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(26)