Wiese was a late withdrawal from the match against France in Marseille last week and will take over from Kwagga Smith, who will start among the replacements.
Nienaber also handed starts to locks Salmaan Moerat and Marin Orie with Lood de Jager having returned home with a shoulder injury and Eben Etzebeth dropping to the bench.
Andre Esterhuizen comes in at inside centre in a new-look midfield pairing with Damian de Allende, who switches to outside centre in place of Jesse Kriel.
The other positional switch sees Franco Mostert move from lock to flanker in place of Pieter-Steph du Toit, who is awaiting a disciplinary hearing on Wednesday for a red card received against France for cleaning out a ruck dangerously.
No 8 Evan Roos, meanwhile, will feature on the replacements bench alongside forwards Etzebeth, Smith, and the front row of Steven Kitshoff, Vincent Koch (both props) and Malcolm Marx (hooker) in a split of six forwards and two backs on the bench.
Cobus Reinach (scrumhalf) and Manie Libbok (utility back), in turn, will provide backline cover, with Libbok able to cover flyhalf, centre, wing and fullback.
Springbok team to face Italy in Genoa:
15 – Willie le Roux (Toyota Verblitz) – 81 caps, 65 pts (13t)
14 – Cheslin Kolbe (Toulon) – 22 caps, 61 pts (10t, 1c, 3p)
13 – Damian de Allende (Wild Knights) – 68 caps, 45 pts (9t)
12 – Andre Esterhuizen (Harlequins) – 10 caps, 0pts
11 – Kurt-Lee Arendse (Vodacom Bulls) – 5 caps, 20 pts (4t)
10 – Damian Willemse (DHL Stormers) – 25 caps, 25 pts (1t, 4c, 4p)
9 – Faf de Klerk (Canon Eagles) – 44 caps, 30 pts (5t, 1c, 1p)
8 – Jasper Wiese (Leicester Tigers) – 19 caps, 5 pts (1t)
7 – Franco Mostert (Honda Heat) – 61 caps, 15 pts (3t)
6 – Siya Kolisi (captain, Cell C Sharks) – 73 caps, 45 pts (9t)
5 – Marvin Orie (DHL Stormers) – 8 caps, 0 pts
4 – Salmaan Moerat (DHL Stormers) – 2 caps, 0 pts
3 – Frans Malherbe (DHL Stormers) – 56 caps, 5 pts (1t)
2 – Bongi Mbonambi (Cell C Sharks) – 53 caps, 55 pts (11t)
1 – Ox Nche (Cell C Sharks) – 17 caps, 0 pts
Replacements:
16 – Malcolm Marx (Kubota Spears) – 57 caps, 65 pts (13t)
17 – Steven Kitshoff (DHL Stormers) – 69 caps, 5 pts (1t)
18 – Vincent Koch (Stade Francais) – 40 caps, 0 pts
19 – Eben Etzebeth (Cell C Sharks) – 108 caps, 15 pts (3t)
20 – Kwagga Smith (Shizuoka Blue Revs) – 29 caps, 15 pts (3t)
21 – Evan Roos (DHL Stormers) – 1 cap, 0 pts
22 – Cobus Reinach (Montpellier) – 22 caps, 40 pts (8t)
23 – Manie Libbok (DHL Stormers) – 1 cap, 0 pts
Springbok record against Italy:
Played 15; Won 14; Lost 1; Points for: 701, Points against: 174; Tries scored 96, Tries conceded 14; Highest score 101-0; Biggest win 101 points. Win % 93%.
Milestones:
- Siya Kolisi is the second most capped Springbok captain having led the side in 43 Test matches.
- Eben Etzebeth is the second most capped Springbok lock with 108 Tests.
Miscellaneous:
- The total Test caps for the Springbok starting line-up is 544.
- There are 255 caps in the backline, with 289 caps among the forwards. On the bench there are a further 327 caps.
- The average caps per player in the backline are 36, the forwards 36, while the players on the bench average 40.
