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Nat Commun. 2018 Aug 27;9(1):3450. doi: 10.1038/s41467-018-05899-7.

HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction.

Author information

1
Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA. hakiyama@bu.edu.
2
Department of Pathology, Boston University School of Medicine, Boston, MA, 02118, USA.
3
Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA.
4
Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, 02118, USA.
5
Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA. rgummulu@bu.edu.

Abstract

Low levels of type I interferon (IFN-I) are thought to be a driving force for immune activation and T-cell exhaustion in HIV-1 infected individuals on combination antiretroviral therapy (cART), though the causative mechanisms for persistent IFN-I signaling have remained unclear. Here, we show Rev-CRM1-dependent nuclear export and peripheral membrane association of intron-containing HIV-1 RNA, independent of primary viral sequence or viral protein expression, is subject to sensing and signaling via MAVS, resulting in IFN-I-dependent pro-inflammatory responses in macrophages. Additionally, HIV-1 intron-containing-RNA-induced innate immune activation of macrophages leads to upregulation of inhibitory receptor expression and functional immune exhaustion of co-cultured T cells. Our findings suggest that persistent expression of HIV-1 intron-containing RNA in macrophages contributes to chronic immune activation and T-cell dysfunction and that use of HIV RNA expression inhibitors as adjunct therapy might abrogate aberrant inflammation and restore immune function in HIV-infected individuals on cART.

PMID:
30150664
PMCID:
PMC6110775
DOI:
10.1038/s41467-018-05899-7
[Indexed for MEDLINE]
Free PMC Article

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