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Saints assistant coach Dave Rotheram, who is standing in for Ian Millward, has decided to rest Vinnie Anderson, Jamie Lyon and Nick Fozzard against the 500-1 outsiders.
York, who lost to Huddersfield in the quarter-finals last season, have not beaten Saints for 59 years and they have lost on their last 10 trips to Knowsley Road.
The game at Wigan will be special for Frenchman Jerome Guisset, who will line up against a host of former team-mates and fellow internationals.
The 26-year-old forward began his career with St Esteve, the club which merged with XIII Catalan to form UTC, and turned down the chance to rejoin them before he signed for Wigan three months ago.
But Guisset insists there will be no divided loyalties as he looks to share in some cup glory after several near-misses with his former club Warrington.
?I played in three semi-finals in the last five years with Warrington, including last year against Wigan,? he said.
?Wigan is renowned for Challenge Cup success in the past. It?s a competition that is very important to the club and it?s an extra special game for me.?
Pia, who lost 50-16 at Huddersfield last season, will be relying on Test scrum-half Maxime Greseque to spring a shock at Headingley. He scored 63 points in his side?s earlier victories over London Skolars and Keighley.
The Donkeys could be in for some hard toil against the 11-8 cup favourites but Leeds coach Tony Smith says his side will not underestimate their visitors.
?I know they will be keen to do both themselves and French rugby league proud and we will show them the utmost respect,? he said.
?With the arrival of Perpignan in Super League next season, French rugby league is on a real high at the moment and the fact that they have three teams still in the competition at this stage shows the current resurgence of the game in France. Long may it continue.?
Toulouse, the third French club in the last 16, appear to have the best chance of making it to the quarter-finals. They take on Doncaster at home on Saturday afternoon hoping to become only the second French team to reach the last eight.
The tie of the round takes place on Saturday at the KC Stadium, where Hull host Bradford, the 2003 winners.
The Bulls won this season?s league encounter between the sides but Robbie Paul, who has led his side to five cup finals in the last 10 years, is expecting a close game.
?Anyone who has experienced success in the cup will tell you it is something you would play your whole career for but this game for us this week is going to be very tough,? he said.
?Hull are a good side with some great players, they are at home, they play in a fantastic stadium with one of the most vocal crowds in the world of sport and with the history between us in the past two years it?s all pointing to a very close game.
?In saying that, the reality is that all the pressure is on them because they are at home and a lot is expected of them. They have not been going that well, by their own standards, despite the fact they are sitting third in the table.?
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Thanks to www.superleague.co.uk for another great article.