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

Hisashi Akiyama (), Caitlin M. Miller, Chelsea R. Ettinger, Anna C. Belkina, Jennifer E. Snyder-Cappione and Suryaram Gummuluru ()
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Hisashi Akiyama: Boston University School of Medicine
Caitlin M. Miller: Boston University School of Medicine
Chelsea R. Ettinger: Boston University School of Medicine
Anna C. Belkina: Boston University School of Medicine
Jennifer E. Snyder-Cappione: Boston University School of Medicine
Suryaram Gummuluru: Boston University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05899-7

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