Caveolin 1 (Cav-1), the scaffold protein of a specific membrane lipid raft called caveolae, has been reported to suppress HIV-1 replication. However, the mechanism by which Cav-1 inhibits HIV replication remains unclear. In this study, we investigated the mechanism by which Cav-1 inhibits HIV replication at the level of gene expression. Our results show that Cav-1 represses viral gene expression and that this suppression involves the NF-¿B pathway. We used several approaches in different cell types, including primary CD4(+) T cells and macrophages, to demonstrate the role of nuclear factor ¿B (NF-¿B) in Cav-1-mediated inhibition of viral expression. A mutational analysis of the cis-acting element shows that the two NF-¿B sites in the U3 region of the long terminal repeat (LTR) are critical for Cav-1-mediated inhibition of viral expression. In the presence of Cav-1, phosphorylation of IKKß, IKKa, I¿Ba, and NF-¿B p65 is dramatically reduced, while viral gene expression is suppressed. In addition, translocation of NF-¿B p65 to the nucleus decreases substantially in the presence of Cav-1. Furthermore, significant inhibition of NF-¿B activation and binding to target DNA are evident in the presence of Cav-1. These results establish evidence that Cav-1 inhibits HIV replication by transcriptional repression of viral gene expression and contributes to HIV's persistent infection of macrophages.

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