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THE ROLE OF LIPOPROTEINS IN THE INFECTIOUS CYCLE OF HCV IN CHIMERIC MICE
R Steenbergen1,4, J Lewis1, M Joyce2, D Douglas1, G Francis3, N Kneteman1
1Surgical Medical Research Institute; 2Medical Microbiology and Immunology; 3Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton; 4Funded by the NCRTP-HepC
BACKGROUND: Studies in chimpanzees revealed that the highest infectivity of Hepatitis C Virus (HCV), derived from patient plasma, is associated to a relatively low density on a sucrose gradient. HCV found at higher densities on these gradients is poorly infectious in chimpanzees. The low density of infectious HCV implicates that HCV is associated to a lipid containing particle. Most data indicate that this particle is a low or very low density lipoprotein (LDL or VLDL). In vitro data suggest association of HCV to apolipoprotein B (apoB), the main apolipoprotein of VLDL and LDL.
HYPOTHESIS: We hypothesize that the association of HCV to apoB containing lipoproteins is essential for a successful infectious cycle of HCV, in chimeric mice and in humans.
OUTCOMES: Mice naturally have very low levels of apoB containing lipoproteins. We have shown that the lipoprotein profiles of chimeric mice (SCID/Alb-uPA mice with human liver engraftments, which are susceptible to HCV infection) approach human lipoprotein profiles, with an increase in the apoB containing lipoproteins. This shift correlates to the degree of human chimerism in these mice, and to their infection success. We are investigating lipoprotein association of HCV in serum derived from infected chimeric mice, in patient serum, and in cell culture derived HCV, and we are studying infectivity of the different fractions.
CONCLUSIONS: The humanization of lipoprotein profiles in chimeric mice appears to play a role in the successful infection cycle of HCV in chimeric mice.