Background:
Previous studies suggested that pegylated interferon α2b (peg-IFN-α2b) and the broadly neutralizing antibodies (bNabs) 3BNC117 and 10-1074 may contribute to cure-related strategies. We evaluated the effect of a 26-week immunotherapy course with peg-IFN-α2b+bNAbs in the cytotoxic function and activation of natural killer (NK) cell subsets in persons with HIV infection (PWH) that participated in the BEAT 2 study (NCT03588715).
Methods:
Fourteen PWH receiving suppressive antiretroviral therapy (ART, <50 HIV-1 copies/ml) underwent ART interruption (ATI) while receiving a 26-week immunotherapy course of peg-IFN-α2b+bNAbs. Peripheral blood mononuclear cells (PBMC) were collected prior to ATI/immunotherapy (ART alone, time-point 1), on ART+4 weeks peg-IFN-α2b (time-point 2), and on ATI+26 weeks peg-IFN-α2b+bNAbs (time-point 3). Fresh PBMC were used in 51Cr release assays for assessment of antibody-dependent cell-mediated cytotoxicity (ADCC) against NK-resistant lymphoblastic target cell line prior and after in vitro stimulation with gp120, and for direct cytotoxicity against MHC-cell null cancer target cell line prior and after in vitro stimulation with IFN-α. Cryopreserved PBMC were used for immunophenotypic characterization by flow cytometry of NK cell subsets and of markers associated with NK activation, inhibition or maturation (e.g. CD38, NKp46, NKG2A, Siglec 7, Siglec 9, CD57). Statistics were performed by JMP 15.
Results:
Immunotherapy did not affect IFN-α-induced NK direct cytotoxicity but resulted in a decrease in gp120-mediated ADDC. Reduced ADCC was observed together with an increase in the cytokine producing CD56hi and in CD56lo/+CD16- % of CD56+ NK cells, and a decrease in the cytotoxic CD56lo/+CD16+ % of CD56+, suggesting that decrease in the expression of Fc receptor CD16 on NK could be associated with lower ADCC function. These findings were supported by a negative correlation between ADCC and CD56lo/+CD16- % of lymphocytes after IFN-α immunotherapy (end of step 2). Finally, the gp120-induced ADCC decrease was observed together with a decrease in the maturation/cytotoxicity marker CD57 in CD56lo/+CD16+ NK cells, despite an increase in activation (CD38, NKp46) and inhibition (NKG2A, Siglec 7) markers.
Conclusions:
In PWH, combined immunotherapy with peg-IFN-α2b+bNAbs resulted in no effect on IFN-α-induced NK direct cytotoxicity and an unexpected decrease in gp120-induced ADCC and in circulating CD16+ NK cell subsets.
