Regulation of human retroviral latency by the NF-κB/IκB family: Inhibition of human immunodeficiency virus replication by IκB through a Rev-dependent mechanism

The cellular transcription factor NF-κB stimulates human immunodeficiency virus type 1 (HIV-1) transcriptional initiation, but its role in the retroviral life cycle has not been fully defined. In this report, we show that IκBα acts as a cellular inhibitor of human retroviral replication through a discrete mechanism, independent of its effect on HIV transcription. IκBα inhibited HIV replication and gp160 expression by negatively regulating Rev function, most likely acting through a cellular factor involved in Rev transactivation. A similar effect was observed with human T leukemia virus I, in which IκBα inhibited Rex function. In contrast, no effect was observed on the replication of a DNA virus, adenovirus type 5. The NF-κB/IκB regulatory pathway therefore modulates human retroviral replication by regulating a program of cellular gene expression required for several steps in the viral life cycle, including not only viral transcription but also RNA export. This interaction between cellular and viral gene products suggests that NF-κB plays a broader role in the regulation of human retroviral replication, providing a previously unrecognized link between two important regulators of HIV gene expression and common NF-κB-dependent programs of gene expression used by human retroviruses.