A Comparison of Murine Leukemia Viruses That Escape from Human and Rhesus Macaque TRIM5s

To better understand the binding mechanism of TRIM5 to retrovirus capsid, we had previously selected N-tropic murine leu-kemia virus (N-MLV) mutants escaping from rhesus macaque TRIM5 (rhTRIM5) by passaging the virus in rhTRIM5-ex-pressing cells and selecting for nonrestricted variants. To test the commonality of the findings from the rhTRIM5 study, we have now employed a similar genetic approach using human TRIM5 (huTRIM5). Consistent with the rhTRIM5 study, the mapped huTRIM5 escape mutations were distributed across the capsid exterior, confirming the extended binding surface be-tween virus and restriction factor. Compared to the results of the previous study, fewer escape mutations were identified, with particular mutants being repeatedly selected. Three out four huTRIM5 escape variants showed resistance to all primate TRIM5s tested, but two of them sacrificed viral fitness, observations that were not made in the rhTRIM5 study. Moreover, differences in amino acid changes associated with escape from hu- and rhTRIM5s suggested a charge dependence of the restric-tion by different TRIM5s. Taken together, these results suggest that the recognition of the entire capsid surface is a general strategy for TRIM5 to restrict MLV but that significantly different specific interactions are involved in the binding of TRIM5 from different species to the MLV capsid core. Capsid (CA)-binding retrovirus restriction factors have arisenon at least five occasions in the course of evolution. Their independent evolution is testament to the utility of such factors, either to limit endogenous retrovirus amplification or to inhibi