Background
Stem-like, proliferative TCF-1+, CD8⁺ T cell responses have been linked to post-intervention control (PIC) of HIV. In ACTG A5386, we evaluated the impact of the IL-15 superagonist N-803, with or without bNAbs during ART, on T cell function and phenotype. In parallel, we examined which T cell features were associated with PIC.
Methods
T cells were phenotypically profiled by flow cytometry. Antigen-specific responses were assessed following stimulation with pooled peptides (Gag, Pol, Env, Nef) by IFNγ and granzyme B ELISPOT, proliferation (dye dilution), and combined Intracellular Cytokine Stain (ICS; IFNγ, IL-2, TNFα) and Activation Induced Marker (AIM; 41BB, CD69, CD40L) assays. For these analyses, data from 30 available participants from the N-803 only (n=10) and N-803 + bNAb (n=20) arms were combined. Assays were performed on samples collected at baseline (Wk0) and 8wks after the last of 8 N-803 doses (Wk32). Within-participant changes were assessed using Wilcoxon matched-pairs signed rank tests.
Results
Three of 30 participants achieved PIC (2 N-803, 1 N-803+bNAb), maintaining HIV RNA levels <1,000cpm for >24 weeks following analytical treatment interruption. Two features distinguishing PICs have thus far been identified (all 3 controllers in the top ≥75th percentile of participants): (i) At both wk0 and wk32, high Gag- and Nef-specific CD8+ T cell proliferation and Gag- and Pol-specific CD4+ T cell proliferation. (ii) At wk32 only: high TCF-1+ frequencies within total CD8+ T cells. Across all 30 participants receiving N-803, treatment was associated with shifts in total CD8+ T cell phenotypes from baseline: Increase in TCF-1+ cells (mean 64.6% vs 66.7%, P=0.011), including TCF-1+H3K27me3low (28.4% vs 32.3%, P<0.0001), and stem cell memory (TSCM) CD8+ T cells (2.4% vs 3.0%, P=0.0106). Concordantly, TOX+PD-1+ (13.0% vs 10.8%, P<0.0001) and terminal effector (TTE) CD8+ T cells (16.4% vs 14.96%, P<0.01) decreased. The frequency of polyfunctional HIV-specific CD8+ T cells co-producing IFNγ, IL-2, and TNFα increased (0.02% vs 0.04%, P=0.027), whereas ELISPOT and proliferation responses did not change significantly relative to baseline.
Conclusions
In A5386, immunologic changes observed following N-803±bNAb showed modest shifts toward stem-like, less exhausted, and polyfunctional CD8⁺ T cell states. Among these features, higher frequencies of TCF-1⁺ CD8⁺ T cells appeared enriched in participants who achieved PIC, linking intervention-associated immune remodeling to post-ATI outcomes.
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