TRIMCyp generated by retrotransposition of a cyclophilin A inserting into TRIM5 locus, has been identified in owlmonkey and most of Old World monkeys (OWM). Owl monkey TRIMCyp (omTRIMCyp) inhibits HIV-1 infectionby direct interaction with viral capsid and indirect innate immune induction, whereas most of TRIMCyps fromOWM cannot inhibit HIV-1, and the impact of which on immunoregulation is largely unknown. Here we reportedthat omTRIMCyp induces NF-κB, AP-1 and IFN-β activation in a dose-dependent manner, while TRIMCyp fromnorthern pig-tailed macaque (npmTRIMCyp) does not activate NF-κB and moderately enhances AP-1 and IFN-βactivities. The Cyclophilin A (CypA) domain plays an important role in omTRIMCyp-mediated NF-κB activation,and RBCC domains have a synergetic effect. We further indicated the mechanism by which npmTRIMCyp unableto activate NF-κB is that npmTRIMCyp hardly phosphorylates IκBα, different from omTRIMCyp which drama-tically induces IκBα phosphorylation. Ubiquitination activity of omTRIMCyp was greater than npmTRIMCyp,although both could be ubiquitylated. Given that npmTRIMCyp neither interacts with viral capsid resulting insusceptibility to HIV-1 infection, nor activates NF-κB that is indispensable to HIV-1 provirus transcription, weproposed a model that npmTRIMCyp may play an important role in HIV-1 infected northern pig-tailed macaquewith latency.