It is still unclear as to who the villains will be. The Covenant Remnant is still active, however they are at their breaking point. The Covenant will most likely be destroyed toward the beginning of the game, considering Locke is seen trying to fight off Jul 'Mdama and capture Halsey, and we know from the Sprint vidocs that Halsey is in UNSC custody toward the beginning of the game. So the Covenant are somewhat of a threat to both Locke and Chief, but probably not for long…
Now we also have the Prometheans. We know that Locke is fighting them, but we still don’t know about the Chief. Considering the Warden Eternal “called” the Chief, and let him on board the Guardian, Chief may or not be enemies of the Prometheans. Or perhaps they are taking a Guilty Spark approach, so they are neither friends nor enemies. People were also originally thinking that the Guardians will be the enemies… but we know now that Guardians are basically gigantic A.I. vehicles.
So who is the real threat here? My guess is that ONI will eventually become the antagonists. Hunt the Truth has been leading up to this. ONI is almost seemingly forming some type of empire or something, and they are doing some pretty radical things. Perhaps a civil war breaks out? The E3 demo had a few small hints at that, such as the creepy lava-filled ONI building at the end during the logo, with sinister music playing in the background (now I could be digging a little too deep with that one). We basically know at this point that ONI will be involved somehow, and probably not in a good way.
Also, it would make sense for the flood to return at some point. We have no indication of their return in Halo 5, however we also have no indication that they won’t return. As the Precursors were the ones who created the concept of the Mantle, and the Didact is probably not with the Chief, it would also make sense if something like the Timeless One made an appearance in a future Halo game, maybe to guide Chief and humanity to becoming the next Forerunners, though I’m not really sure what the relationship of the Precursors and humans would be. Who knows, maybe I’m wrong. Just speaking my mind. 
*Edit: Its also pretty obvious that Locke will eventually join with the Chief. He one of the two protagonists after all, and it would be pretty stupid to have all of this character build up just to get rid of him or have him turn bad.
