Interleukin-21 and anti-α4β7 dual therapy during ART promotes immunological and microbiome responses in SIV-infected macaques

Samuel D. Johnson; Maria Pino; Arpan Acharya; Julien A. Clain; Deepanwita Bose; Kevin Nguyen; Justin Harper; Francois Villinger; Mirko Paiardini; Siddappa N. Byrareddy

doi:10.1172/jci.insight.184491

Interleukin-21 and anti-α4β7 dual therapy during ART promotes immunological and microbiome responses in SIV-infected macaques

Samuel D. Johnson,¹ Maria Pino,² Arpan Acharya,¹ Julien A. Clain,² Deepanwita Bose,³ Kevin Nguyen,² Justin Harper,² Francois Villinger,³ Mirko Paiardini,² and Siddappa N. Byrareddy¹

Published February 4, 2025 - More info

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Abstract

Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Further, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4⁺ T-cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points post-ATI. Additionally, following post-ATI, dual-treated RMs showed immunological benefits, including T-cell preservation and lower PD-1⁺ central memory T-cell (TCM) frequency. Notably, PD-1⁺ TCMs were associated with reservoir size, which predicted viral loads (VLs) post-ATI. Finally, 16S rRNA sequencing revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1⁺ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.

Interleukin-21 and anti-α4β7 dual therapy during ART promotes immunological and microbiome responses in SIV-infected macaques

Samuel D. Johnson,¹ Maria Pino,² Arpan Acharya,¹ Julien A. Clain,² Deepanwita Bose,³ Kevin Nguyen,² Justin Harper,² Francois Villinger,³ Mirko Paiardini,² and Siddappa N. Byrareddy¹

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Interleukin-21 and anti-α4β7 dual therapy during ART promotes immunological and microbiome responses in SIV-infected macaques

Samuel D. Johnson,1 Maria Pino,2 Arpan Acharya,1 Julien A. Clain,2 Deepanwita Bose,3 Kevin Nguyen,2 Justin Harper,2 Francois Villinger,3 Mirko Paiardini,2 and Siddappa N. Byrareddy1

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Samuel D. Johnson,¹ Maria Pino,² Arpan Acharya,¹ Julien A. Clain,² Deepanwita Bose,³ Kevin Nguyen,² Justin Harper,² Francois Villinger,³ Mirko Paiardini,² and Siddappa N. Byrareddy¹