Changes in Innate and Permissive Immune Responses after HBV Transgenic Mouse Vaccination and lLong-Term-siRNA Treatment

Abstract

BackgroundCurrently, no licensed therapy can thoroughly eradicate hepatitis B virus (HBV) from the body, including interferon α and inhibitors of HBV reverse-transcription. Small interfering RNA (siRNA) seem to be a promising tool for treating HBV, but had no effect on the pre-existing HBV covalently closed circular DNA. Because it is very difficult to thoroughly eradicate HBV with unique siRNAs, upgrading the immune response is the best method for fighting HBV infection. Here, we aim to explore the immune response of transgenic mice to HBV vaccination after long-term treatment with siRNAs and develop a therapeutic approach that combines siRNAs with immunopotentiators.Methodology/Principal FindingsTo explore the response of transgenic mice to hepatitis B vaccine, innate and acquired immunity were detected after long-term treatment with siRNAs and vaccination. Antiviral cytokines and level of anti-hepatitis B surface antigen antibody (HBsAg-Ab) were measured after three injections of hepatitis B vaccine.ResultsFunctional analyses indicated that toll-like receptor-mediated innate immune responses were reinforced, and antiviral cytokines were significantly increased, especially in the pSilencer4.1/HBV groups. Analysis of CD80+/CD86+ dendritic cells in the mouse liver indicated that dendritic cell antigen presentation was strengthened. Furthermore, the siRNA-treated transgenic mice could produce detectable HBsAg-Ab after vaccination, especially in the CpG oligonucleotide vaccine group.Conclusions/SignificanceFor the first time, our studies demonstrate that siRNAs with CpG HBV vaccine could strengthen the immune response and break the immune tolerance status of transgenic mice to HBV. Thus, siRNAs and HBV vaccine could provide a sharp double-edged sword against chronic HBV infection.

Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy

“…However, despite the availability of a hepatitis B virus vaccine, 400 million individuals are chronically infected with hepatitis B virus. Continuous RNAi‐mediated silencing in combination with other anti‐viral therapeutics to simultaneously reduce liver damage and eliminate hepatitis B virus is thought to be an improved approach for curing chronic hepatitis B virus infection (Li et al, 2013; Ren et al, 2013). Hence, several in vivo preclinical studies have evaluated the combination of potent RNAi and anti‐ hepatitis B virus therapeutics (Li et al, 2014; Shih et al, 2015).…”

Conservation and variability of hepatitis B core at different chronic hepatitis stages

“…Gene therapy has emerged as one of the most promising strategies for blocking disease progression, and results from studies investigating the potential of small interfering RNA (siRNA) systems as adjuvant therapy are encouraging [6] . SiRNA is a double-stranded noncoding RNA [with an optimal length of 21 nucleotides (nt)] that interacts with target messenger RNA, promoting its degradation and silencing of the gene [7] .…”

Treatment options beyond IFNα and NUCs for chronic HBV infection: expectations for tomorrow

“…A CpG containing HBsAg vaccine was shown to overcome hyporesponsiveness normally seen in immunized orangutans . Finally, long‐term treatment of transgenic mice with siRNAs targeting the C and S regions produced detectable anti‐HBs after normal vaccination combined with concurrent CpG injection . Whether similar responses are observed in human trials must await further investigation.…”