Youtube does not operate with knowledge of actual specific infringement on their site. The DMCA creates a two-pronged obligation on hosting providers: they must respond to takedowns, and they can't operate with knowledge of actual specific unaddressed infringement. Not only did MegaUpload do that, but they (a) paid their users to upload content they knew to be infringing, and (b) themselves used the service to upload and download content they knew to be infringing.