The TLR7-IRF-5 axis sensitizes memory CD4<sup>+</sup> T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez; Xavier Dagenais-Lussier; Linh Thuy Mai; Tanja Stögerer; Sharada Swaminathan; Stephane Isnard; Matthew R. Rice; Betsy J. Barnes; Jean Pierre Routy; Julien van Grevenynghe; Simona Stager

doi:10.1172/jci.insight.167329

The TLR7-IRF-5 axis sensitizes memory CD4⁺ T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez,¹ Xavier Dagenais-Lussier,¹ Linh Thuy Mai,¹ Tanja Stögerer,¹ Sharada Swaminathan,¹ Stephane Isnard,² Matthew R. Rice,³ Betsy J. Barnes,⁴ Jean Pierre Routy,² Julien van Grevenynghe,¹ and Simona Stager⁵

Published May 25, 2023 - More info

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Abstract

HIV-1 infection is characterized by a strong inflammatory environment, tissue disruption, and a progressive decline in CD4⁺ T cell count. Despite treatment with antiretroviral therapy (ART), the majority of persons living with HIV (PLWH) maintain residual levels of inflammation, low degree of immune activation, and higher sensitivity to cell death in their memory CD4⁺ T-cell compartment. To date, the mechanisms responsible for this high sensitivity remain elusive. We have identified the transcription factor IRF-5 to be involved in impairing the maintenance of murine CD4⁺ T cells in a chronic inflammatory environment. Here, we investigate whether IRF-5 also contributes to memory CD4⁺ T cell loss during HIV-1 infection.

We show that TLR7 and IRF-5 were upregulated in memory CD4⁺ T cells from PLWH, when compared with naturally protected elite controllers and HIV^free participants. TLR7 was upstream of IRF-5, promoting Caspase 8 expression in CD4⁺ T cells from ART HIV-1⁺ but not from HIV^free participants. Moreover, IRF-5 and TLR7 expression inversely correlated with CD4⁺ T cell counts in primary HIV infection. Interestingly, the TLR7-IRF-5 axis acted synergistically with the Fas/FasL pathway, suggesting that TLR7 and IRF-5 expression in ART HIV-1⁺ memory CD4⁺ T cells represents an imprint that predisposes cells to Fas-mediated apoptosis. This predisposition could be blocked using IRF-5 inhibitory peptides. Thus, we propose IRF-5 blockade as a possible therapy to prevent memory CD4⁺ T cell loss in PLWH.

The TLR7-IRF-5 axis sensitizes memory CD4⁺ T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez,¹ Xavier Dagenais-Lussier,¹ Linh Thuy Mai,¹ Tanja Stögerer,¹ Sharada Swaminathan,¹ Stephane Isnard,² Matthew R. Rice,³ Betsy J. Barnes,⁴ Jean Pierre Routy,² Julien van Grevenynghe,¹ and Simona Stager⁵

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The TLR7-IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez,1 Xavier Dagenais-Lussier,1 Linh Thuy Mai,1 Tanja Stögerer,1 Sharada Swaminathan,1 Stephane Isnard,2 Matthew R. Rice,3 Betsy J. Barnes,4 Jean Pierre Routy,2 Julien van Grevenynghe,1 and Simona Stager5

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The TLR7-IRF-5 axis sensitizes memory CD4⁺ T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez,¹ Xavier Dagenais-Lussier,¹ Linh Thuy Mai,¹ Tanja Stögerer,¹ Sharada Swaminathan,¹ Stephane Isnard,² Matthew R. Rice,³ Betsy J. Barnes,⁴ Jean Pierre Routy,² Julien van Grevenynghe,¹ and Simona Stager⁵