Intriguingly, both in the absence and presence of MTb co-infection, disruption of NF-κB site II consistently resulted in greater suppression of virus replication than disruption of NF-κB site I. Consistent with these findings, synthetic reporter assays have previously shown that these two sites have distinct roles in driving transcription. The downstream NF-κB site I binding site, which is directly upstream of three highly conserved Sp binding sites, appears to enhance Sp protein recruitment to the LTR [71]–[73]. Because NF-κB site I overlaps the NFAT5 binding site, it is possible that loss of NF-κB binding to this site is mitigated, at least in part, by increased NFAT5 binding to the mutated site. This hypothesis is consistent with our quantitative DNase I footprinting analysis that shows that specific disruption of NF-κB site I results in enhanced binding of NFAT5 to the LTR.