Host MicroRNAs-221 and -222 Inhibit HIV-1 Entry in Macrophages by Targeting the CD4 Viral Receptor

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Robert Lodge, Jérémy A. Ferreira Barbosa, Félix Lombard-Vadnais, Julian C. Gilmore, Alexandre Deshiere, Annie Gosselin, Tomas Raul Wiche Salinas, Mariana G. Bego, Christopher Power, Jean-Pierre Routy, Petronela Ancuta, Michel J. Tremblay, Éric A. Cohen
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 RNA sequencing (RNA-seq) to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two microRNAs upregulated 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 tumor necrosis factor alpha (TNF-α), an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-α-treated macrophages by enhancing CD4 expression and increased HIV-1 replication and spread in macrophages by countering TNF-α-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.

Graphical abstract

Teaser

Using RNA-seq, Lodge et al. compared microRNA profiles of virus producing and bystander macrophages in HIV-1-infected cultures. Among those enhanced in bystanders were microRNAs-221 and -222. These microRNAs are part of an anti-HIV response in bystanders, potentiated by TNF-α activation, which inhibits HIV-1 entry by reducing CD4 expression.


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