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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 CD4n + 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.n Results::A significantly higher proportion of CD56n dimCD16n dim/- NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56n dimCD16n dim/- NK cells was inversely correlated with CD4n + T-cell counts in INRs before ART (n r = -0.344, n P = 0.050). The more CD69-expressing NK cells there were, the lower the CD4n + T-cell counts and ΔCD4, and these correlations were observed in INRs after ART ( n r = -0.416, n P = 0.019; n r = -0.509, n P = 0.003, respectively). Additionally, CD69-expressing CD56n dimCD16n dim/- NK cells were more abundant in INRs than those in IRs (n P = 0.018) after ART, both of which had an inverse association trend towards significance with CD4n + T-cell counts. The expression of the activating receptors NKG2C, NKG2D, and NKp46 on CD56n dimCD16n dim/- NK cell subsets were higher in IRs than that in INRs after 4 years of ART (all n P < 0.01). Strong inverse correlations were observed between CD69 expression and NKG2C, NKG2A n -NKG2Cn +, NKG2D, and NKp46 expression on CD56n dimCD16n dim/- NK cells in INRs after ART (NKG2C: r = -0.491, n P = 0.004; NKG2An -NKG2Cn +: n r = -0.434, n P = 0.013; NKG2D: n r = -0.405, n P = 0.021; NKp46: n r = -0.457, n P = 0.008, respectively).n Conclusions::INRs had a larger number of CD56n dimCD16n dim/ - NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56n dimCD16n dim/- NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56n dimCD16n dim/- NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.n “,”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 CD4n + 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.n Results::A significantly higher proportion of CD56n dimCD16n dim/- NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56n dimCD16n dim/- NK cells was inversely correlated with CD4n + T-cell counts in INRs before ART (n r = -0.344, n P = 0.050). The more CD69-expressing NK cells there were, the lower the CD4n + T-cell counts and ΔCD4, and these correlations were observed in INRs after ART ( n r = -0.416, n P = 0.019; n r = -0.509, n P = 0.003, respectively). Additionally, CD69-expressing CD56n dimCD16n dim/- NK cells were more abundant in INRs than those in IRs (n P = 0.018) after ART, both of which had an inverse association trend towards significance with CD4n + T-cell counts. The expression of the activating receptors NKG2C, NKG2D, and NKp46 on CD56n dimCD16n dim/- NK cell subsets were higher in IRs than that in INRs after 4 years of ART (all n P < 0.01). Strong inverse correlations were observed between CD69 expression and NKG2C, NKG2A n -NKG2Cn +, NKG2D, and NKp46 expression on CD56n dimCD16n dim/- NK cells in INRs after ART (NKG2C: r = -0.491, n P = 0.004; NKG2An -NKG2Cn +: n r = -0.434, n P = 0.013; NKG2D: n r = -0.405, n P = 0.021; NKp46: n r = -0.457, n P = 0.008, respectively).n Conclusions::INRs had a larger number of CD56n dimCD16n dim/ - NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56n dimCD16n dim/- NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56n dimCD16n dim/- NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.n