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

Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Furthermore, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized that 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 after ATI. Additionally, following 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) after ATI. Finally, 16S rRNA-Seq 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.