Abstract
Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%–1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7–82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205–0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%–51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%–64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%–9.7%; and % p24 reduction median: 13.84, IQR: 9.863%–17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.
Highlights
In human immunodeficiency virus (HIV) infection, strategies to reduce the cellular reservoir of HIV are urgently required
We attempted to generate antibodydependent cellular cytotoxicity (ADCC)-mediating antibodies and assessed their potency to assist in natural killer (NK) cell-mediated lysis of reactivated HIV reservoirs
By using the gp140-specific memory B cells of the long-term non-progressors (LTNPs) with and without plasma ADCC activity, we identified nine antibodies with potent ADCC activity, five of which were tested for their ability to facilitate NK cell-mediated lysis of Env-reactivated latent reservoirs
Summary
In human immunodeficiency virus (HIV) infection, strategies to reduce the cellular reservoir of HIV are urgently required. Our previous study has shown functional memory B-cell compartment in Indian LTNPs. Considering the available information, we conducted the present study to answer two questions: 1) Whether memory B cells from LTNPs could differentiate into plasma cells and generate HIV-specific antibodies, and 2) if so, whether these antibodies can mediate ADCC activity and facilitate natural killer (NK) cell-mediated lysis of reactivated HIV reservoirs. We showed that the HIV-gp140-specific memory B cells sorted from the LTNPs were successfully differentiated into plasma cells in a 10-day culture and secreted anti-gp140specific antibodies These antibodies showed the ability to mediate ADCC and lyse the Env-reactivated latently infected resting memory CD4+ T cells via NK cells. These antibodies have a higher potential to lyse reactivated latent reservoirs
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