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In a total of nine changes from the side that defeated England at the Millennium Stadium, Gatland also drafts in experienced back-rowers Ryan Jones, who takes the captaincy, and Martyn Wililams, who will win his 99th cap.
But it is the return of Jones from a toe injury; Halfpenny after four months out with an ankle injury; and Byrne who has had a knee problem that will gladden Gatland the most with the World Cup fast approaching.
Byrne’s return to the No.15 shirt also sees James Hook shift to fly-half, where he impressively orchestrated Wales’ second-half performance in their 19-9 defeat of England.
Hook will be partnered in the midfield by Jonathan Davies, who replaces the injured Gavin Henson, with Jamie Roberts switching to his favoured inside centre role.
Osprey Richard Hibbard, who has also had a lengthy spell on the sidelines after shoulder surgery, comes in for Lloyd Burns at hooker to pack down alongside clubmates Jones and Paul James while Bradley Davies enters the second row in place of Luke Charteris.
Back-rowers Toby Faletau and Sam Warburton – both standout performers against England – drop out of the 22 as does veteran winger Shane Williams.
But although Gatland wants to see his see build on the momentum of Saturday’s victory, he is adamant his starting XV against South Africa on September 11 is yet to be set in stone.
He said: “Criteria for selection has been about putting together a side to win the game, but also about giving some players the opportunity to impress and, therefore, bid for selection for the World Cup.
“In some areas we are also looking at combinations with that opening game against South Africa on 11 September always kept in mind.
“Beating the Pumas on Saturday would also mean we retain that all important winning momentum going into the World Cup.
“But there are still many places up for grabs on that plane to New Zealand and the players all know they need to perform against the Pumas in order to further their own as well as the national cause.”
15. Lee Byrne – Clermont Auvernge
14. Leigh Halfpenny – Cardiff Blues
13. Jonathan Davies – Scarlets
12. Jamie Roberts – Cardiff Blues
11. George North – Scarlets
10. James Hook – Perpignan
9. Tavis Knoyle – Scarlets
1. Paul James – Ospreys
2. Richard Hibbart – Ospreys
3. Adam Jones – Ospreys
4. Bradley Davies – Cardiff Blues
5. Alun Wyn Jones - Ospreys
6. Dan Lydiate – Newport Gwent Dragons
7. Martyn Williams – Cardiff Blues
8. Ryan Jones – Ospreys
16. Huw Bennett – Ospreys
17. Ryan Bevington – Ospreys
18. Andy Powell – Sale Sharks
19. Justin Tipuric – Ospreys
20. Lloyd Williams – Cardiff Blues
21. Stephen Jones – Scarlets
22. Aled Brew – Newport Gwent Dragons