Interleukin-10 inhibits HIV-1 LTR-directed gene expression in human macrophages through the induction of cyclin T1 proteolysis

Abstract

Regulation of HIV-1 replication in human monocytes/macrophages occurs at multiple levels including transcription of the proviral genome, which depends on virally encoded Tat protein. Interleukin-10 (IL-10), an anti-inflammatory cytokine which is up-regulated during disease progression of AIDS, has been reported to suppress HIV-1 replication in macrophages at a post-entry stage of the virus life cycle. Our previous studies have demonstrated that Tat function is regulated during the differentiation of monocyte-derived macrophages (MDMs) in a manner that correlates with the early induction and subsequent shut-off of its cellular cofactor cyclin T1. Here, we report that IL-10 down-regulates cyclin T1 expression through the induction of proteasome-mediated proteolysis in human macrophages. Using a reporter virus that is deficient in Tat function, we also demonstrate that IL-10 inhibits HIV-1 gene expression in a Tat-dependent manner. Together, these results suggest that the down-regulation of cyclin T1, and consequently Tat function, contributes to the suppressive effect of IL-10 on HIV-1 replication in human macrophages.