A Novel Host-Based Immunotherapy for the Suppression of HBV and HCV Replication: Heat-Killed Caulobacter crescentus...

Background: Hepatitis B and C viral infections remain a significant global health challenge, despite the implementation of an effective direct-acting antiviral (DAAs) and nucleos(t)ide analogues (NAs). Current HBV therapy is not curative as stopping therapy usually leads to active disease in most patients requiring long-term treatment. Although current HCV-DAAs are highly effective they fall short due to arising drug-resistance and have limited ability to avert re-infections. Furthermore, current HCV DAA treatments lead to the reactivation of occult HBV infection, compromising the effectiveness of current antiviral therapies, and increasing the risk of severe liver complications like cirrhosis and hepatocellular carcinoma. In addition, current treatments do not restore the immune dysfunction, a characteristic of chronic HBV infection. Given the global burden of disease, there is an urgent need for more effective therapy that can shorten the duration of treatment and achieve high rates of HBsAg reduction. Combining an antiviral to reduce viral antigen burden and an immunomodulator to boost the immune response could provide an effective treatment for HBV/HCV infections. Methods: In this study, we explored the potential of a novel bacterial therapeutic agent, heat-killed Caulobacter crescentus (HKCC), as an alternative and/or adjunct host-based therapy for HCV and HBV infections. Here, we have investigated the antiviral effects of the HKCC-stimulated human PBMCs using in vitro HCV and HBV infection models to assess viral replication, viral relapse responses, protein expression, and cytotoxicity. Results: Our findings reveal that HKCC induced a multi-functional cytokine response (IFN, TNF, IL-2, IL-10, IL-6, IL-17A, and IL-22) in PBMCs obtained from multiple healthy donors. Supernatants collected from these HKCC-stimulated human PBMCs, alone and in combination with antivirals, strikingly inhibited HCV replication and viral relapse responses without inducing any cytotoxic effects on HCV-1a replicon cells. In addition, these PBMC supernatants, with or without antivirals, led to the suppression of HBV DNA replication and inhibited HBsAg and HBeAg production in HepG 2.2.15 cells. Conclusions: In conclusion, HKCC is a promising candidate for eliminating HBV and HCV infections, and warrants further investigation to potentially contribute to the development of a novel host-based immunotherapy.