Increased early activation of CD56(dim)CD16(dim/-) 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) and 34 immunological responders (IRs) with improved 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 CD56(dim)CD16(dim/-) NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56(dim)CD16(dim/-) 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 CD56(dim)CD16(dim/-) 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 CD56(dim)CD16(dim/-) 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, NKG2A(-)NKG2C(+), NKG2D, and NKp46 expression on CD56(dim)CD16(dim/-) NK cells in INRs after ART (NKG2C: r = –0.491, P = 0.004; NKG2A(-)NKG2C(+): 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 CD56(dim)CD16(dim/-) NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56(dim)CD16(dim/-) NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56(dim)CD16(dim/-) NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.