Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 27, Issue -, Pages 1103-1115Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2022.01.020
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The study aimed to design a novel immunomodulator to subvert immune tolerance to HBV, showing promising results in inducing strong immune responses against the virus by targeting CpG oligonucleotide to lymphoid organs in a mouse model of chronic HBV infection.
Despite the existence of a prophylactic vaccine against hepatitis B virus (HBV), chronic hepatitis B virus (CHB) infection remains the leading cause of cirrhosis and liver cancer in developing countries. Because HBV persistence is associated with insufficient host immune responses to the infection, development of an immunomodulator as a component of therapeutic vaccination may become an important strategy for treatment CHB. In the present study, we aimed to design a novel immunomodulator with the capacity to subvert immune tolerance to HBV. We developed a lymphoid organ-targeting immunomodulator by conjugating a naturally occurring, lipophilic molecule, a-tocopherol, to a potent CpG oligonucleotide adjuvant pharmacophore. This approach resulted in preferential trafficking of the a-tocopherol-conjugated oligonucleotide to lymphoid organs where it was internalized by antigen-presenting cells (APCs). Moreover, we show that conjugation of the oligonucleotides to a-tocopherol results in micelle-like structure formation, which improved cellular internalization and enhanced immunomodulatory properties of the conjugates. In a mouse model of chronic HBV infection, targeting CpG oligonucleotide to lymphoid organs induced strong cellular and humoral immune responses that resulted in sustained control of the virus. Given the potency and tolerability of an could potentially be broadly applied for therapeutic vaccine development.
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