The macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses

Sita Ramaswamy; Hisashi Akiyama; Jacob Berrigan; Andrés A. Quiñones-Molina; Alex J. Olson; Yunhan Chen; YanMei Liang; Andrew J. Henderson; Archana Asundi; Manish Sagar; Suryaram Gummuluru

doi:10.1172/JCI187663

The macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses

Sita Ramaswamy,¹ Hisashi Akiyama,¹ Jacob Berrigan,¹ Andrés A. Quiñones-Molina,¹ Alex J. Olson,² Yunhan Chen,² YanMei Liang,² Andrew J. Henderson,¹ Archana Asundi,² Manish Sagar,¹ and Suryaram Gummuluru¹

Published June 10, 2025 - More info

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Abstract

Despite effective antiretroviral therapy (ART), transcriptionally competent HIV-1 reservoirs persist 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 mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling protein (MAVS)-mediated type I interferon (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 IRF5 activation in macrophages. Suppression of MDA5, but not RIG-I expression nor disruption of 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 MDMs from older (>50 years) individuals exhibit constitutively higher levels of IRF5 expression compared to 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 pro-inflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.

The macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses

Sita Ramaswamy,¹ Hisashi Akiyama,¹ Jacob Berrigan,¹ Andrés A. Quiñones-Molina,¹ Alex J. Olson,² Yunhan Chen,² YanMei Liang,² Andrew J. Henderson,¹ Archana Asundi,² Manish Sagar,¹ and Suryaram Gummuluru¹

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The macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses

Sita Ramaswamy,1 Hisashi Akiyama,1 Jacob Berrigan,1 Andrés A. Quiñones-Molina,1 Alex J. Olson,2 Yunhan Chen,2 YanMei Liang,2 Andrew J. Henderson,1 Archana Asundi,2 Manish Sagar,1 and Suryaram Gummuluru1

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Sita Ramaswamy,¹ Hisashi Akiyama,¹ Jacob Berrigan,¹ Andrés A. Quiñones-Molina,¹ Alex J. Olson,² Yunhan Chen,² YanMei Liang,² Andrew J. Henderson,¹ Archana Asundi,² Manish Sagar,¹ and Suryaram Gummuluru¹