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Assessing the Innate Sensing of HIV-1 Infected CD4+ T Cells by Plasmacytoid Dendritic Cells Using an Ex vivo Co-culture System.
Published on: September 1, 2015
The macrophage-intrinsic MDA5/IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses
Sita Ramaswamy1, Hisashi Akiyama1, Jacob Berrigan1
1Department of Virology, Immunology & Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
Abstract:
Despite effective antiretroviral therapy, transcriptionally competent HIV-1 reservoirs remain and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though the mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling (MAVS) protein-mediated type I IFN responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent interferon regulatory factor 5 (IRF5) activation in macrophages. Suppression of MDA5 but not retinoic acid-inducible gene I expression nor disruption of the endosomal TLR pathway abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and monocyte-derived macrophages (MDMs) from older (>50 years) individuals exhibited constitutively higher levels of IRF5 expression compared with younger (<35 years) individuals, and HIV-1 icRNA-induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression, suggesting that IRF5 functions as a major mediator of proinflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.
Insights
Melanoma differentiation-associated protein 5 (MDA5) senses HIV-1 intron-containing RNA (icRNA) in macrophages, driving type I interferon responses. This pathway, involving IRF5, contributes to chronic inflammation in older people living with HIV.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Persistent HIV-1 reservoirs cause immune activation despite antiretroviral therapy (ART).
- HIV-1-infected macrophages mediate chronic innate immune activation via unclear mechanisms.
- HIV-1 intron-containing RNA (icRNA) cytoplasmic expression activates MAVS-mediated type I interferon (IFN) responses.
Purpose of the Study:
- To elucidate the role of MDA5 in sensing HIV-1 icRNA and initiating innate immune responses.
- To investigate the downstream signaling pathways, including IRF5, involved in HIV-1 icRNA-induced inflammation.
- To explore age-related differences in HIV-1 icRNA sensing and pro-inflammatory responses.
Main Methods:
- Macrophages were used to study HIV-1 icRNA sensing pathways.
- MDA5 and RIG-I expression and function were modulated.
- Interferon (IFN) and IP-10 responses were measured.
- Monocytes and macrophages from younger and older individuals were analyzed.
Main Results:
- MDA5, not RIG-I or endosomal TLRs, is essential for sensing HIV-1 icRNA and inducing type I IFN and IP-10 in macrophages.
- MDA5-dependent induction of IP-10 requires IRF5 activation.
- Macrophages from older individuals exhibit higher constitutive IRF5 and enhanced HIV-1 icRNA-induced IP-10 production.
- Ablation of IRF5 attenuated the enhanced inflammatory response in older macrophages.
Conclusions:
- MDA5 is a key sensor of HIV-1 icRNA in macrophages, initiating MAVS-dependent type I IFN and IP-10 responses.
- IRF5 is a critical mediator of the pro-inflammatory cascade downstream of MDA5-mediated HIV-1 icRNA sensing.
- Dysregulation of the MDA5-IRF5 pathway may contribute to chronic inflammation in older people living with HIV.
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