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

Nature Communications
Hisashi AkiyamaSuryaram Gummuluru

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.

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Citations

May 23, 2019·PLoS Pathogens·Matthew GagneAndrew J Henderson
Jun 24, 2020·The Journal of Clinical Investigation·Yang-Hui Jimmy YehYa-Chi Ho
Feb 14, 2019·MBio·Oya Cingöz, Stephen P Goff
Jul 28, 2020·Proceedings of the National Academy of Sciences of the United States of America·Carina ElsnerChristine Goffinet
Nov 30, 2019·Viruses·Maïwenn BergezDirk Lindemann
Jan 24, 2020·Cells·Xin YinSumit K Chanda
Aug 10, 2019·Frontiers in Immunology·Sarah Beth Nodder, Suryaram Gummuluru
Jul 8, 2020·Viruses·Hisashi Akiyama, Suryaram Gummuluru
Oct 20, 2020·The Journal of Infectious Diseases·Alex OlsonManish Sagar
Dec 11, 2020·Journal of Virology·Hisashi AkiyamaSuryaram Gummuluru
Mar 3, 2021·Nature Microbiology·Stephanie V RebensburgMamuka Kvaratskhelia
May 26, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Rodolfo NazittoAlan H Diercks
May 7, 2021·Journal of Virology·Caroline PassaesAsier Sáez-Cirión

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Methods Mentioned

BETA
Flow
flow cytometry
PCR
DropArray
FACS
confocal microscopy

Software Mentioned

GraphPad Prism
ImageJ

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