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CDK9/cyclin T1, a key enzyme in HIV-1 transcription, is negatively regulated by 7SK RNA and the HEXIM1 protein. Dephosphorylation of CDK9 on Thr186 by protein phosphatase 1 (PP1) in stress-induced cells or by protein phosphatase M1A in normally growing cells activates CDK9. Our previous studies showed that l-HV-1 Tat protein binds to PP1 through the Tat Q35VC F38 sequence, which is similar to the PP 1-binding RVXF motif and that this interaction facilitates HIV1 transcription. In the present study, we analyzed the effect of expression of the central domain of nuclear inhibitor of PP1 (cdNIPP1) in an engineered cell line and also when cdNIPPi was expressed as part of HIV-1 pNL4-3 in place of nef~ Stable expression of cdNIPP1 increased CDK9 phosphorylation on Thr'86 and the association of CDK9 with 7SK RNA, The stable expression of cdNIPP1 disrupted the interaction of Tat and PP1 and inhibited HIV-1 transcription. Expression of cdNIPP1 as a part of the HIV-1 genome inhibited HIV-1 replication. Our study provides a proof-of-concept for the future development of PP1-targeting compounds as inhibitors of HIV-1 replication. [ABSTRACT FROM AUTHOR]