NK cell depletion in bispecific antibody therapy is associated with lack of HIV control after ART interruption

Abstract

NK cell; Bispecific antibody therapy; HIV

Cèl·lules NK; Teràpia d'anticossos biespecífics; VIH

Células NK; Terapia d'anticuerpos biespecíficos; VIH:es

HIV infection remains incurable as the virus persists within a latent reservoir of CD4+T cells. Novel approaches to enhance immune responses against HIV are essential for effective control and potential cure of the infection. In this study, we designed a novel tetravalent bispecific antibody (Bi-Ab32/16) to simultaneously target the gp120 viral protein on infected cells, and the CD16a receptor on NK cells. In vitro, Bi-Ab32/16 triggered a potent, specific, and polyfunctional NK-dependent response against HIV-infected cells. Moreover, addition of the Bi-Ab32/16 significantly reduced the latent HIV reservoir after viral reactivation and mediated the clearance of cells harboring intact proviruses in samples from people with HIV (PWH). However, the in vivo preclinical evaluation of Bi-Ab32/16 in humanized mice expressing IL-15 (NSG-Hu-IL-15) revealed a significant decline of NK cells associated with poor virological control after ART interruption. Our study underscores the need to carefully evaluating strategies for sustained NK cell stimulation during ART withdrawal.

This study was supported by the Spanish Secretariat of Science and Innovation, FEDER funds (RTI2018-101082-B-I00, PID2021-123321OB-I00, PDC2022.133836-100), two Gilead fellowships (GLD21/00049, GLD22/00152) as well as partially funded by the PI20/00160 grant from the Spanish Health Institute Carlos III, co-funded by ERDF/ESF, “A way to make Europe”/“Investing in your future”, the CNS2022-135549 grant, funded by MCIN/AEI/10.13039/501100011033 and by the European Union «Next Generation EU»/PRTR. M.B. is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179 and CPII22/00005). N.S-G is supported by the Spanish Secretariat of Science and Innovation Ph.D. fellowship (PRE2019-087393). We would like to thank Dr. Julia G. Prado from IrsiCaixa Institute for AIDS Research for generating the viral stock R5-BaL and Jorge Díaz from the Comparative Medicine and Bioimage Centre of Catalonia (CMCIB) for its excellent technical assistance with in vivo animal studies. The funders had no role in study design, data collection, and analysis, the decision to publish, or preparation of the manuscript.