Efficacy of cationic lipid–DNA complexes (CLDC) on hepatitis B virus in transgenic mice

Abstract

Cationic lipid-DNA (non-coding) complexes (CLDC) are activators of the innate immune response that increase survival of rodents with some acute viral infections and cancers. CLDC were evaluated for their ability to impact viral DNA levels in transgenic mice carrying an infectious clone of hepatitis B virus (HBV). Mice used in the studies were diet-restricted as nursing pups from solid food, because the expression of HBV DNA in the liver was increased above background levels in some mice with this restriction. Survival surgery was performed on these mice to obtain liver biopsies from which to select animals with suitable levels of liver HBV DNA for entry into the experimental protocols. Intravenous administration of 5 microg/mouse of CLDC on days 1, 7 and 13 reduced liver HBV DNA to similar low levels achieved with the positive control, adefovir dipivoxil. In a subsequent experiment, the same treatment schedule was used to determine that the minimal effective CLDC dose was between 0.5 and 0.05 microg/mouse. Selective cytokines were increased in the livers of CLDC-treated compared to placebo-treated mice in a dose-responsive manner. CLDC were effective in reducing liver HBV DNA and could be considered for further evaluation in other hepatitis models.

Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

“…It is not surprising that the CLNC component of our LANACs worked therapeutically against WEEV; CLDCs can rapidly induce potent antiviral activity across a wide range of viral infections (13,30,31). We previously reported that CLDCs (liposome-ODN complexes) protect against s.c. challenge with WEEV in the CD-1 mouse model when administered 24 h before infection (13).…”

Vaccine approaches conferring cross-protection against influenza viruses

“…Formulation of seasonal influenza vaccine with liposome-based adjuvants has been shown to induce cross-protection in animal studies[83]. A novel cationic liposome-based adjuvant JVRS-100 [comprising double-stranded plasmid DNA and octadecenoyloxy[ethyl-2-heptadecenyl-3-hydroxyethyl] chloride (DOTIM) and cholesterol as liposome–DNA complexes (CLDC)] has been shown to possess adjuvant activity in several studies in mice and non-human primates[77,95,96]. An inactivated A/PR/8/34 (H1N1) influenza vaccine formulated with JVRS-100 adjuvant was shown to induce cross-protective immunity in mice against challenge with a sublethal dose of X-31 influenza virus.…”

Alkoxyalkyl Esters of 9-( S )-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo

“…3). The amount of liver HBV DNA expressed in transgenic mice was variable between animals, and the results for the lower drug concentrations were less reliable because of the background of the assay (21). Nevertheless, the dynamic range of the HBV DNA on May 11, 2018 by guest http://aac.asm.org/ assay is sufficient to detect dose-response relationships.…”

“…To assess the effect of alkoxyalkyl esterification of (S)-HPMPA on its in vitro and in vivo anti-HBV activity, we synthesized HDP-(S) C]HPMPA, we also evaluated the oral pharmacokinetics and the level of drug exposure in the plasma, livers, and spleens of mice. Finally, the oral activities of the HDP, ODE, and 15M-HDP esters of (S)-HPMPA were assessed in HBV transgenic mice (15,17,21); and their activities were compared with the in vivo activity of adefovir dipivoxil, a compound licensed for use for the treatment of HBV infection.…”

“…Liver HBV DNA was quantified by Southern blot hybridization or quantitative PCR (21). The PCR primers do not distinguish between different replicative intermediates or chromosomal transgenic DNA, but the background PCR signal of transgenic DNA is sufficiently low for the quantitation of extrachromosomal HBV DNA.…”