The two-time AFC Champions League runner-up is on six points, five ahead of an Istiklol side who has struggled for form on the continental stage.
Istiklol impressed in its opening match, holding Qatar's Al Duhail SC to a goalless draw but has found points hard to come by since.
A fighting performance against Al Nassr wasn't enough as the Saudi Arabian side walked away with a 3-1 win while Persepolis was too strong when the sides met two weeks ago, with the Iranian champion triumphing 2-0.
Persepolis bounced back admirably after succumbing to a 2-0 defeat against Al Nassr.
It edged Al Duhail 1-0 in a tight encounter in Doha and showed its quality in the reverse fixture against Istiklol and will be determined to keep pace at the top with Al Nassr with another win.