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

• Published in: Nature communications Vol. 9; no. 1; pp. 3450 - 12
• Main Authors: Akiyama, Hisashi, Miller, Caitlin M., Ettinger, Chelsea R., Belkina, Anna C., Snyder-Cappione, Jennifer E., Gummuluru, Suryaram
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/31; 13/95; 14; 14/19; 14/35; 38; 38/77; 38/88; 631/250/255/1901; 631/326/596/2553; 631/326/596/2555; 631/326/596/2557; Amino acid sequence; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Cell activation; Exhaustion; Gene expression; HIV; HIV-1 - genetics; HIV-1 - immunology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate - genetics; Immunity, Innate - physiology; Inflammation; Interferon; Interferon Type I - metabolism; Introns - genetics; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; multidisciplinary; Myeloid Cells - metabolism; Nuclear transport; Nucleotide sequence; Proteins; Recovery of function; Ribonucleic acid; RNA; RNA - genetics; RNA, Viral - genetics; Science; Science (multidisciplinary); Signaling; T-Lymphocytes - metabolism; Therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05899-7

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. Type I Interferon is thought to be a driving force for immune activation and T cell exhaustion during HIV infection. Here the authors show that intron-containing HIV RNA induces innate immune activation resulting in associated T cell dysfunction.