Background: Charles V (Spanish: Carlos; German: Karl; Italian: Carlo; Latin: Carolus; Dutch: Karel; French: Charles,  24 February 1500 - 21 September 1558) was ruler of both the Spanish Empire as Charles I from 1516 and the Holy Roman Empire as Charles V from 1519, as well as of the lands of the former Duchy of Burgundy from 1506. He stepped down from these and other positions by a series of abdications between 1554 and 1556. Through inheritance, he brought together under his rule extensive territories in western, central, and southern Europe, and the Spanish viceroyalties in the Americas and Asia.
Context: Much of Charles's reign was taken up by conflicts with France, which found itself encircled by Charles's empire while it still maintained ambitions in Italy. In 1520, Charles visited England, where his aunt, Catherine of Aragon, urged her husband, Henry VIII, to ally himself with the emperor. In 1508 Charles was nominated by Henry VII to the Order of the Garter. His Garter stall plate survives in Saint George's Chapel.  The first war with Charles's great nemesis Francis I of France began in 1521. Charles allied with England and Pope Leo X against the French and the Venetians, and was highly successful, driving the French out of Milan and defeating and capturing Francis at the Battle of Pavia in 1525. To gain his freedom, Francis ceded Burgundy to Charles in the Treaty of Madrid, as well as renouncing his support of Henry II's claim over Navarre.  When he was released, however, Francis had the Parliament of Paris denounce the treaty because it had been signed under duress. France then joined the League of Cognac that Pope Clement VII had formed with Henry VIII of England, the Venetians, the Florentines, and the Milanese to resist imperial domination of Italy. In the ensuing war, Charles's sack of Rome (1527) and virtual imprisonment of Pope Clement VII in 1527 prevented the Pope from annulling the marriage of Henry VIII of England and Charles's aunt Catherine of Aragon, so Henry eventually broke with Rome, thus leading to the English Reformation. In other respects, the war was inconclusive. In the Treaty of Cambrai (1529), called the "Ladies' Peace" because it was negotiated between Charles's aunt and Francis' mother, Francis renounced his claims in Italy but retained control of Burgundy.  A third war erupted in 1536. Following the death of the last Sforza Duke of Milan, Charles installed his son Philip in the duchy, despite Francis's claims on it. This war too was inconclusive. Francis failed to conquer Milan, but he succeeded in conquering most of the lands of Charles's ally, the Duke of Savoy, including his capital Turin. A truce at Nice in 1538 on the basis of uti possidetis ended the war but lasted only a short time. War resumed in 1542, with Francis now allied with Ottoman Sultan Suleiman I and Charles once again allied with Henry VIII. Despite the conquest of Nice by a Franco-Ottoman fleet, the French could not advance toward Milan, while a joint Anglo-Imperial invasion of northern France, led by Charles himself, won some successes but was ultimately abandoned, leading to another peace and restoration of the status quo ante bellum in 1544.  A final war erupted with Francis' son and successor, Henry II, in 1551. Henry won early success in Lorraine, where he captured Metz, but French offensives in Italy failed. Charles abdicated midway through this conflict, leaving further conduct of the war to his son, Philip II, and his brother, Ferdinand I, Holy Roman Emperor.
Question: Who was the first war against?

Answer:
The first war with Charles's great nemesis Francis I of France began in 1521.