{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:07:25Z","timestamp":1779782845620,"version":"3.53.1"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The crosstalk between intestinal epithelial cells (IEC) and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells is essential for the maintenance of mucosal homeostasis, but its role in governing HIV-1 latency\n                      <jats:italic>versus<\/jats:italic>\n                      reactivation in gut-homing\/resident T-cells remains poorly documented. We previously demonstrated that the Th17-lineage cytokine IL-17A transcriptionally reprograms IEC for promoting viral outgrowth in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells of antiretroviral therapy (ART)-treated people with HIV-1 (PWH). These effects coincided with the downregulation of IL-32, a cytokine with documented antiviral properties and identified as a marker for HIV-1 disease progression and cardiovascular disease risk. Here, we aimed to identify modulators of IL-32 expression and to define the impact of IEC expressing IL-32 on HIV-1 outgrowth in neighboring CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells carrying viral reservoirs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      HT-29 IEC were activated with TNF and\/or IL-22, IL-26,\n                      <jats:italic>all<\/jats:italic>\n                      -\n                      <jats:italic>trans<\/jats:italic>\n                      retinoic acid (ATRA) and rosiglitazone (RGZ). CRISPR\/Cas9 gene editing was used to knockout (KO)\n                      <jats:italic>IL32<\/jats:italic>\n                      in IEC, with efficiency\/off-target effect assessments performed using TIDE and whole-genome RNA-Sequencing. IL-32\u03b2\/\u03b3\/\u03f5 mRNA\/protein were quantified by RT-PCR\/ELISA. An IEC-based viral outgrowth assay (VOA) was performed with CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells of ART-treated PWH. Soluble\/intracellular HIV-p24 levels were measured by ELISA\/flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In combination with TNF, IL-22 upregulated IL-32\u03b2\/\u03f5, RGZ increased IL-32\u03b2, ATRA decreased IL-32\u03b2\/\u03b3\/\u03f5, while IL-26 had no impact in IEC. HIV-1 outgrowth in IEC:T-cell co-cultures was not affected by IL-22\/RGZ\/ATRA-mediated changes in IL-32 expression. The analysis of differentially expressed genes in control\n                      <jats:italic>versus IL32KO<\/jats:italic>\n                      IEC revealed minor differences in transcriptional profiles before\/after exposure to TNF, while the IL-32 mRNA\/protein expression was induced by TNF in control but not\n                      <jats:italic>IL32KO<\/jats:italic>\n                      IEC. Finally, TNF-activated control\n                      <jats:italic>versus IL32<\/jats:italic>\n                      KO IEC supported with similar efficacy HIV-1 outgrowth in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells of PWH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified IL-22, ATRA and RGZ as novel regulators of IL-32 expression in TNF-primed IEC and demonstrated that pharmacological and genetic modulation of IL-32 expression in IEC has no major impact on HIV-1 outgrowth from co-cultured CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells of ART-treated PWH carrying viral reservoirs. By excluding its role in modulating HIV reservoir latency\/reactivation at intestinal barrier level, these results support the idea of testing the potential use of IL-32 as a novel therapeutic target to reduce comorbidities in ART-treated PWH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1769388","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:57:45Z","timestamp":1779782265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological and genetic modulation of IL-32 expression in intestinal epithelial cells does not impact HIV-1 outgrowth in co-cultured CD4+ T-cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Etiene","family":"Moreira Gabriel","sequence":"first","affiliation":[{"name":"Centre hospitalier de l'Universit\u00e9 de Montr\u00e9al (CHUM) Research Centre","place":["Montr\u00e9al, QC, 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