Conversation so far:
what was the name of the country Charles V, the Holy Roman Emperor, had the most issues with?
Much of Holy Roman Emperor Charles V's reign was taken up by conflicts with France, which found itself encircled by Charles's empire while it still maintained ambitions in Italy.

Question: what year did he have his conflict with his nemisis?
Self-contained rewrite: what year did Charles V, Holy Roman Emperor, have his conflict with his nemisis?