Increased early activation of CD56dimCD16dim/- natural killer cells in immunological non-responders correlates with CD4+ T-cell recovery.

BACKGROUND Natural killer (NK) cells play a critical role in suppressing human immunodeficiency virus-1 (HIV-1) infection, but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy (ART) is limited. METHODS We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders (INRs) with poor CD4 T-cell recovery ( 500 cells/μL after 4 years of ART). NK cell phenotype, receptor repertoire, and early activation in INRs and IRs were investigated by flow cytometry. RESULTS A significantly higher proportion of CD56CD16 NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56CD16 NK cells was inversely correlated with CD4 T-cell counts in INRs before ART (r = -0.344, P = 0.050). The more CD69-expressing NK cells there were, the lower the CD4 T-cell counts and ΔCD4, and these correlations were observed in INRs after ART (r = -0.416, P = 0.019; r = -0.509, P = 0.003, respectively). Additionally, CD69-expressing CD56CD16 NK cells were more abundant in INRs than those in IRs (P = 0.018) after ART, both of which had an inverse association trend towards significance with CD4 T-cell counts. The expression of the activating receptors NKG2C, NKG2D, and NKp46 on CD56CD16 NK cell subsets were higher in IRs than that in INRs after 4 years of ART (all P < 0.01). Strong inverse correlations were observed between CD69 expression and NKG2C, NKG2ANKG2C, NKG2D, and NKp46 expression on CD56CD16 NK cells in INRs after ART (NKG2C: r = -0.491, P = 0.004; NKG2ANKG2C: r = -0.434, P = 0.013; NKG2D: r = -0.405, P = 0.021; NKp46: r = -0.457, P = 0.008, respectively). CONCLUSIONS INRs had a larger number of CD56CD16 NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56CD16 NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56CD16 NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.