简介：AbstractBackground:Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART).Methods:From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People’s Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (108 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group.Results:From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P= 0.006) and CD8 level (β = 322.47, P= 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).

简介：AbstractBackground: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 CD56dimCD16dim/- NK cells was observed in INRs than IRs before ART and after 4 years of ART. The number of CD56dimCD16dim/- 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 CD56dimCD16dim/- 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 CD56dimCD16dim/- 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 CD56dimCD16dim/- 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 CD56dimCD16dim/ - NK cells characterized by higher activation levels than did IRs after ART. The increase in the CD56dimCD16dim/- NK cell subset may play an adverse role in immune reconstitution. Further functional studies of CD56dimCD16dim/- NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.