Nanodepots Encapsulating a Latency Reversing Agent and Broadly Neutralizing Antibody Enhance Natural Killer Cell Cytotoxicity Against an in vitro Model of Latent HIV

被引:0
作者
Ghofrani, Joshua [1 ,2 ]
Bowen, Allan [2 ]
Chen, Jie [2 ]
Balakrishnan, Preethi Bala [2 ]
Powell, Allison B. [1 ,2 ]
Cherukula, Kondareddy [2 ]
Cruz, Conrad Russell Y. [2 ,3 ]
Jones, R. Brad [4 ]
Lynch, Rebecca M. [5 ]
Sweeney, Elizabeth E. [2 ,6 ]
Fernandes, Rohan [1 ,2 ,7 ,8 ]
机构
[1] George Washington Univ, Inst Biomed Sci, Sch Med & Hlth Sci, Washington, DC USA
[2] George Washington Univ, George Washington Canc Ctr, Washington, DC USA
[3] Childrens Natl Hosp, Ctr Canc & Immunol Res, Washington, DC USA
[4] Weill Cornell Med, Dept Med, Div Infect Dis, New York, NY USA
[5] George Washington Univ, Sch Med & Hlth Sci, Dept Microbiol Immunol & Trop Med, Washington, DC USA
[6] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Med, Washington, DC USA
[7] George Washington Univ, Sch Med & Hlth Sci, Dept Med, Washington, DC USA
[8] 800 22nd St NW,Sci & Engn Hall,Suite 8410, Washington, DC 20052 USA
来源
INTERNATIONAL JOURNAL OF NANOMEDICINE | 2023年 / 18卷
基金
美国国家卫生研究院;
关键词
latent HIV reservoirs; latency reversing agent; broadly neutralizing antibody; shock and kill strategies; NK cell therapy; PLGA nanodepots; TNF-& alpha; 3BNC117; ACH-2; cells; PLGA-BASED NANOPARTICLES; TUMOR-NECROSIS-FACTOR; MEDIATED CYTOTOXICITY; INFECTION; PROTEINS; ADSORPTION; INDUCTION; RESERVOIR; TOXICITY; DELIVERY;
D O I
10.2147/IJN.S401304
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Purpose: Current antiretroviral therapies (ART) for human immunodeficiency virus (HIV) are not curative, as the virus persists in latent reservoirs, requiring lifelong adherence to ART and increasing the risk of co-morbidities. "Shock and kill" approaches to reactivate HIV from latent reservoirs followed by administration of anti-HIV drugs represent a promising strategy for eradicating latent HIV. To achieve effective shock and kill, we describe a strategy to eradicate the HIV reservoir that combines latency reversing agents (LRAs), broadly neutralizing antibodies (bnAbs), and natural killer (NK) cells. This strategy utilizes a polymer nanodepot (ND) that co-encapsulates the LRA and bnAb to reactivate latent infection and elicit enhanced cytotoxicity from co-administered NK cells.Methods: Poly(lactic-co-glycolic acid) (PLGA) NDs were synthesized using the nanoprecipitation method to co-encapsulate an LRA (TNF-a) and a bnAb (3BNC117) (TNF-a-3BNC117-NDs). ACH-2 cells were used as a cellular model of latent HIV infection. An NK92 subline, genetically modified to constitutively express the Fc receptor CD16, was administered to ACH-2 cells in combination with TNF-a-3BNC117-NDs. ACH-2 cell death and extracellular p24 were measured via flow cytometry and ELISA, respectively.Results: Stable PLGA NDs co-encapsulated TNF-a and 3BNC117 with high efficiencies and released these agents in physiological conditions. NK92 phenotype remained similar in the presence of TNF-a-3BNC117-NDs. TNF-a released from NDs efficiently reactivated HIV in ACH-2 cells, as measured by a 3.0-fold increase in the frequency of intracellular p24 positive cells. Released 3BNC117 neutralized and bound reactivated virus, targeting 57.5% of total ACH-2 cells. Critically, TNF-a-3BNC117-NDs signifi-cantly enhanced NK92 cell-mediated killing of ACH-2 cells (1.9-fold) and reduced extracellular levels of p24 to baseline.Conclusion: These findings suggest the therapeutic potential of our novel ND-based tripartite strategy to reactivate HIV from latently infected cells, generate an HIV-specific site for bnAb binding, and enhance the killing of reactivated HIV-infected target cells by NK92 cells.
引用
收藏
页码:4055 / 4066
页数:12
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