Differential expression of microRNAs in productively HIV-1 infected and bystander macrophages in culture.

Macrophages are heterogeneous immune cells with distinct origins, phenotypes, functions and tissue localization. Their susceptibility to HIV-1 is subject to variations from permissiveness to resistance, owing in part to regulatory microRNAs. Here, we used RNAseq to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two micro-RNAs up regulated in bystander macrophages, miR-221 and miR-222, were identified as negative regulators of CD4 expression and CD4-mediated HIV-1 entry. Both microRNAs were enhanced by TNF-a, an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-a-treated macrophages by enhancing CD4 expression, and increased HIV-1 replication and spread in macrophages by countering TNF-a-enhanced miR-221/miR-222 expression in bystander cells. In line with these findings, HIV-1-resistant intestinal myeloid cells express higher levels of miR-221 than peripheral blood monocytes. Thus, miR-221/miR-222 act as effectors of the antiviral host response activated during macrophage infection that restrict HIV-1 entry. Overall design: Macrophages derived from the blood of 3 different adults (n=3 adults) were used. MicroRNAseq was performed on uninfected, productively HIV-1 infected (GFP+) and bystander (GFP-) macrophages.