Background
Chronic inflammation contributes to immune dysregulation in people with HIV (PWH), even during suppressive antiretroviral therapy (ART). While IL-1b is a key inflammatory mediator, its blockade has not been mechanistically studied in this context. We investigated the immunologic effects of IL-1b inhibition using Canakinumab (Cana), a monoclonal antibody targeting IL-1b, in ART-suppressed PWH.
Methods
Ten participants received a single 150 mg subcutaneous dose of Cana. Peripheral blood was collected at baseline, 4 weeks, and 8 weeks post-treatment. We performed a multi-Omic analysis that included plasma cytokine profiling, bulk RNA-sequencing of sorted CD4+ T cells, and single cell RNAseq of PBMCs to assess changes in immune signaling pathways and HIV reservoir size, quantified as total HIV DNA copies per 106 CD4+ T cells.
Results
Six participants (“virologic responders” [VR]) showed a significant reduction in HIV reservoir size (23-52%, p=0.0319), while four (“non-responders” [VNR]) did not. Only VR exhibited increased IFNg post-treatment (p=0.038), and the magnitude of this increase correlated with reservoir decline (r=-0.76, p=0.015). RNAseq of sorted CD4+ T cells confirmed that post treatment VR have heightened expression of Type I IFNs and antiviral effectors (i.e., IFITM3) with known anti-HIV activity which can render CD4+ T cells refractory to infection and reservoir reseeding; these correlated with a greater reduction in reservoir. Single cell sequencing revealed significantly reduced target genes of IL-1 signaling pathway post-Cana in all immune subsets in VR vs. VNR, suggesting differences in inflammatory signaling or IL-1b pathway responsiveness between VR and VNR. CD8 T cell sub-clustering revealed a cluster increased in VR exhibiting an enhanced stemness profile (i.e., target genes of TCF7L2, EZH2) while exhibiting high EOMES activity, a regulator of effector function. CD8s from VR also had a lower frequency of PD-1+ cells, a marker of exhaustion, by flow cytometry
Conclusions
This first-in-human study shows that IL-1β blockade can induce an IFN-mediated antiviral state in CD4+ T cells and enhance the longevity and functional capacity of CD8+ T cells, potentially improving immune control of HIV and informing future cure strategies. These mechanisms can be used to enhance the efficacy of other immunotherapies in HIV