A new character introduced in the fanfiction could be the main antagonist. This character could be from a rival faction and sees Issei as a threat. They might use mind - control or other devious means to make Issei betray his friends and then use his 'betrayal' as a way to undermine the group as a whole.
It could be an old enemy of the group who has a personal vendetta against Issei. This antagonist might be jealous of Issei's power or popularity within the group and plots to turn everyone against him. They could spread false rumors or create false evidence to make it seem like Issei has betrayed the group.
Even one of Issei's friends could turn into an antagonist in a way that causes Issei to be seen as the betrayer. For example, if a friend is secretly power - hungry and frames Issei for trying to steal power or resources from the group. This would lead to Issei being wrongly accused and having to fight against his former friends.
In certain fanfictions, fallen angels may act as antagonists. They could be trying to disrupt the relationship between Akeno and Issei or simply cause chaos in the devil world where they live.
Other vampires might be his main antagonists. They could see Issei as a threat, perhaps because he's a new vampire with different ideas or powers. Or they might want to use him for their own gain.
A group of vampire hunters could also be the antagonists. They might not be able to tell the difference between Issei and a full - blooded vampire and target him. They could be very zealous in their mission to wipe out all vampires and view Issei as just another one to be hunted down.
In this kind of fanfiction, the Fallen Angels could be main antagonists. They might see Naruto and Sasuke as threats to their plans in the DxD world.
The devils who oppose Naruto's presence and his new - found influence in the DxD world could be main antagonists. They might see him as a threat to their power structure and the way things are done in their society.
The Khaos Brigade could be a major antagonist. Their goal of causing chaos would put them at odds with Gohan's sense of justice.
The devils who oppose Gilgamesh's presence in the Highschool DxD world could be main antagonists. They might see him as a threat to their power and influence in the school.
Perhaps it could be a group of bullies from Issei's school days. They used to pick on him and now he's coming back to make them pay.
It could be an old enemy of Issei's that he never fully defeated. This enemy, having bided their time, finally manages to kill Issei. They could be a powerful devil from a rival faction who saw Issei as a threat to their power and plans.
The devils who oppose Grayfia's family could be the main antagonists. They might see Grayfia's brother - in - law as a weak link or a potential threat to their power. So they would try to get rid of him or manipulate him for their own gains.