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Background:  We conducted a study to evaluate the effect of treatment interruption on T, NK or DC frequency and function in HIV-1 infected subjects with long-term antiretroviral therapy (ART)-mediated viral suppression.

Methods:  HIV-1-infected subjects on ART were evaluated at baseline, week 4 and week 6 following treatment interruption (n = 7, ≥ 3 drugs, CD4 count > 350 cells/mm³, HIV-1 RNA < 400 copies/mL for > 8 weeks prior to treatment interruption), as well as at re-suppression (HIV-1 RNA < 50 copies/mL) upon ART re-initiation. Clinical parameters as well as T, NK, and DC phenotype and function were assessed by 4-color flow cytometry and standard ⁵¹Cr release assay (results expressed respectively as number of cells and area under the curve for effector:target ratios of 50:1, 25:1, and 12:1). Statistics were performed with JMP 4.

Results:  The reactivation of viral replication did not significantly alter the number of mature CD161⁺/CD56⁺/CD16⁺ NK cells, CD11c⁺ DC, or CD123⁺ DC. However, a significant increase in the percentage of activated (HLA-DR⁺) NK cells (p = 0.04, median 19.4 [IQR 12.3] at baseline; 25.3 [IQR 12.4] at week 6 of treatment interruption) was observed together with a drop in the number of immature CD161⁺/CD56^–/CD16^– NK cell subset (p = 0.02, median 18.3 [IQR 15.9] at baseline; 9.4; [IQR 8.6] at week 6 treatment interruption) indicating acute changes within the NK cell populations upon viral replication. By contrast, CD4 T-cell count rapidly decreased upon ART interruption, but was restored upon ART-mediated re-suppression. Viral replication did alter CD4 T-cell activation as indicated by an up-regulation of CD38 expression. Consistent with the retention of mature NK and DC subsets, spontaneous and CpG-2216 stimulated NK cell-mediated cytotoxicity was maintained in the presence of viral replication suggesting that an acute viremia following short ART interruption does not adversely affect NK cytotoxic function.

Conclusions:  Viral replication following ART interruption is not associated with a direct impairment of DC and NK cell-mediated responses, but results in rapid activation of NK cells. These findings support the hypothesis that loss of cellular innate immune function in chronically viremic individuals is due to viral-mediated secondary effects and not to direct effects of viral replication. Our data also identify the innate effector cell subsets as potential targets for immunotherapy (i.e., CpG, IFN-γ) shortly after therapy interruption based on their retained number and effector function despite of acute viral replication.

Keywords: HIV-1; NK; ART