Increased Early Activation of CD56dimCD16dim/- NK Cells in INRs

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Increased Early Activation of CD56dimCD16dim/- Natural Killer Cells in Immunological Non-Responders Correlates with CD4+ T-Cell Recovery

Human immunodeficiency virus type 1 (HIV-1) infection remains a significant global health challenge, even in the era of effective antiretroviral therapy (ART). While ART suppresses viral replication and improves CD4+ T-cell counts in most individuals, 15%–30% of patients fail to restore adequate CD4+ T-cell levels despite prolonged viral suppression. These patients, termed immunological non-responders (INRs), face heightened risks of AIDS and non-AIDS-related complications, underscoring the need to identify mechanisms driving incomplete immune recovery. Natural killer (NK) cells, pivotal components of innate immunity, play critical roles in antiviral defense and shaping adaptive immune responses. Recent research highlights the contribution of NK cell dysfunction to HIV pathogenesis, but the relationship between NK cell dynamics and CD4+ T-cell recovery in INRs remains poorly understood.

This study explored differences in NK cell subset distribution, activation status, and receptor expression between INRs and immunological responders (IRs) before and after four years of ART. Using flow cytometry, researchers analyzed peripheral blood mononuclear cells (PBMCs) from 66 HIV-1-infected patients (32 INRs, 34 IRs) and 35 healthy controls (HCs). Key findings revealed that INRs exhibited a persistent expansion of the CD56dimCD16dim/- NK cell subset, elevated NK cell activation, and distinct receptor profiles compared to IRs. These abnormalities correlated inversely with CD4+ T-cell recovery, suggesting a detrimental role for dysregulated NK cells in immune reconstitution failure.

Expansion of CD56dimCD16dim/- NK Cells in INRs

NK cells were classified into four subsets based on CD56 and CD16 expression: CD56brightCD16dim/-, CD56dimCD16dim/-, CD56dimCD16bright, and CD56-CD16bright. The CD56dimCD16dim/- subset, characterized as an intermediate maturation stage with cytotoxic potential, was significantly elevated in INRs compared to IRs both before ART (median frequency: 31.0% vs. 23.3%, P = 0.019) and after four years of ART (40.4% vs. 30.2%, P = 0.011). In contrast, IRs and HCs showed similar CD56dimCD16dim/- frequencies post-ART (30.2% vs. 22.8%). Strikingly, the CD56dimCD16dim/- proportion in INRs was inversely correlated with pre-ART CD4+ T-cell counts (Spearman’s r = –0.344, P = 0.050) and pre-ART viral load (r = –0.449, P = 0.010), suggesting a link between this subset and early disease severity.

Notably, the cytotoxic CD56dimCD16bright subset was reduced in HIV-infected patients compared to HCs, both pre- and post-ART (pre-ART INRs: 22.2% vs. 32.5%, P = 0.006). These findings highlight a persistent imbalance in NK cell maturation trajectories in INRs, marked by accumulation of CD56dimCD16dim/- cells and depletion of mature CD56dimCD16bright cells.

Elevated NK Cell Activation in INRs Impedes CD4+ Recovery

CD69, an early activation marker, was used to assess NK cell activation. Post-ART INRs exhibited higher CD69 expression on total NK cells compared to IRs (median: 25.4% vs. 19.7%, P = 0.038) and HCs (25.4% vs. 13.2%, P = 0.012). This activation was particularly pronounced in the CD56dimCD16dim/- subset, where post-ART INRs had significantly higher CD69+ frequencies than IRs (29.4% vs. 20.9%, P = 0.018).

Crucially, CD69 expression on total NK cells inversely correlated with post-ART CD4+ T-cell counts in INRs (r = –0.416, P = 0.019) and the magnitude of CD4+ recovery (ΔCD4: r = –0.509, P = 0.003). A similar trend was observed for CD69+ CD56dimCD16dim/- cells in IRs, though statistical significance was not reached. These results implicate chronic NK cell activation as a contributor to suboptimal immune recovery.

Receptor Expression Profiles Differentiate INR and IR Trajectories

Activating and inhibitory receptor expression on NK cells further distinguished INRs from IRs. Prior to ART, INRs displayed lower NKG2D expression on total NK cells (median: 82.0% vs. 88.9%, P = 0.005) and higher NKp30 levels (72.1% vs. 62.5%, P = 0.003) compared to IRs. After ART, however, receptor disparities shifted to the CD56dimCD16dim/- subset:

  1. Activating Receptors: Post-ART IRs showed higher expression of NKG2C (26.1% vs. 16.6%, P = 0.016), NKG2D (85.3% vs. 78.3%, P = 0.002), and NKp46 (48.4% vs. 38.7%, P = 0.025) on CD56dimCD16dim/- cells compared to INRs.
  2. Inhibitory Receptors: NKG2A expression on CD56dimCD16dim/- cells was reduced in pre-ART INRs versus HCs (9.4% vs. 19.8%, P = 0.012) but normalized post-ART (IRs: 15.5%; INRs: 14.1%).
  3. NKG2A-NKG2C+ Dual Expression: This immunomodulatory phenotype was elevated in post-ART INRs (7.5% vs. 4.8% in HCs, P < 0.0001) but lower than in IRs (7.5% vs. 10.0%, P = 0.030).

Notably, CD69 expression on CD56dimCD16dim/- cells negatively correlated with NKG2C (r = –0.491), NKG2D (r = –0.405), and NKp46 (r = –0.457) in INRs (P < 0.05 for all), suggesting that hyperactivation disrupts functional receptor expression.

Mechanistic Implications and Unresolved Questions

The accumulation of CD56dimCD16dim/- NK cells in INRs may reflect a maladaptive response to chronic immune activation. Increased CD69 expression suggests ongoing stimulation, potentially driven by residual antigen exposure or microbial translocation. Persistent activation could exhaust cytotoxic capacity, as evidenced by reduced NKG2D and NKp46 levels, impairing viral control and CD4+ T-cell support.

The inverse correlation between CD56dimCD16dim/- frequency and pre-ART CD4+ counts further supports a pathogenic role. These cells may directly impair CD4+ recovery through cytokine dysregulation or cytotoxicity against activated T cells—a mechanism previously observed in CD56bright subsets. Alternatively, they may fail to provide necessary helper signals for lymphopoiesis.

Conclusions and Future Directions

This study provides compelling evidence that CD56dimCD16dim/- NK cells are key players in immune reconstitution failure. Their expansion and hyperactivation in INRs correlate with poor CD4+ recovery, while preserved receptor functionality in IRs supports protective immunity. Future work should address:

  1. Functional Characterization: Direct assessment of CD56dimCD16dim/- cytotoxicity, cytokine production, and interactions with CD4+ T cells.
  2. Longitudinal Tracking: Determine whether CD56dimCD16dim/- frequencies predict INR status early in ART.
  3. Therapeutic Targeting: Explore interventions to modulate NK cell maturation or activation, such as IL-15 agonists or checkpoint inhibitors.

By elucidating NK cell dynamics in HIV pathogenesis, this research paves the way for novel strategies to optimize immune recovery in INRs, ultimately reducing morbidity and mortality in this vulnerable population.

doi.org/10.1097/CM9.0000000000001262

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