Andrew Porter and Chris Farrell will make their first Six Nations starts in Ireland's clash with Wales in Dublin on Saturday.
Fast-rising Leinster star Porter will start at tighthead for Ireland, after Tadhg Furlong failed to beat his hamstring injury in time for the Aviva Stadium clash.
Devin Toner starts at lock with Iain Henderson also missing through hamstring trouble.
Porter scrambled from the bench just three minutes into Ireland's 56-19 win over Italy, when Furlong pulled up with his hamstring issue.
The 22-year-old acquitted himself well against the Azzurri, but now faces an entirely different proposition in a serious baptism of Test-match fire for his fifth cap, against Wales this weekend.
Ireland and Leinster have, however, long held high hopes for the physical Under-20s graduate, who only made his Test debut in June 2017.
Munster centre Farrell slots in for Robbie Henshaw, now sidelined for up to four months after a dislocated shoulder.
The former Ulster midfielder won both his Test caps in Ireland's autumn campaign, and will link up with Bundee Aki again, in an inexperienced centre partnership Wales will clearly seek to exploit.
Head coach Joe Schmidt expects both Furlong and Henderson to be fit for Ireland's clash with Scotland in Dublin on March 10.
"Iain was the closer of the two; Iain could probably have played on Saturday," said Schmidt. "But Iain wasn't able to complete training today so we're not going to risk him.
"I just don't think it's worth it with what's coming up and you don't want to put him at risk of further injury. He could definitely play next week, and the week after he will be fine.
"We thought with Tadhg he may well make it, but the progress just stalled a little bit so we said 'let's not chase this, get you right for Scotland in a couple of weeks' time'."
— Irish Rugby (@IrishRugby) February 22, 2018
Ireland team to play Wales
FORWARDS: 1 Cian Healy (Leinster), 2 Rory Best (CAPTAIN, Ulster), 3 Andrew Porter (Leinster), 4 James Ryan (Leinster), 5 Devin Toner (Leinster), 6 Peter O'Mahony (Munster), 7 Dan Leavy (Leinster), 8 CJ Stander (Munster)
BACKS: 9 Conor Murray (Munster), 10 Jonathan Sexton (Leinster), 11 Jacob Stockdale (Ulster), 12 Bundee Aki (Connacht), 13 Chris Farrell (Munster), 14 Keith Earls (Munster), 15 Rob Kearney (Leinster)
REPLACEMENTS: 16 Sean Cronin (Leinster), 17 Jack McGrath (Leinster), 18 John Ryan (Munster), 19 Quinn Roux (Connacht), 20 Jack Conan (Leinster), 21 Kieran Marmion (Connacht), 22 Joey Carbery (Leinster), 23 Fergus McFadden (Leinster)