Journal
CELL REPORTS
Volume 21, Issue 1, Pages 141-153Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.030
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Funding
- Canadian Institutes of Health Research (CIHR) Emerging Team grant [TCO 125271]
- Canadian HIV Cure Enterprise (CanCURE) grant from the CIHR
- Canadian Foundation for AIDS Research
- International AIDS Society [HIG 133050]
- Fonds de Recherche du Quebec-Sante AIDS and Infectious Disease Network
- Canada Research Chair in Neurological Infection Immunity
- Canada Research Chair in Human Immuno-Retrovirology
- IRCM-Universite de Montreal Chair of Excellence in HIV Research
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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-alpha), an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-alpha-treated macrophages by enhancing CD4 expression and increased HIV-1 replication and spread in macrophages by countering TNF-alpha-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.
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