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Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

Sharon D, Chen M, Zhang G, Girgis S, Sis B, Graham D, McDougall C, Wasilenko ST, Montano-Loza A, Mason AL - Liver Int. (2014)

Bottom Line: Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score.Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice.Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.

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Antiretroviral therapy associated with reduced hepatic MMTV RNA and biliary epithelial cell-associated MMTV Gag expression. (A) Antiretroviral therapy modulated MMTV RNA levels in the NOD.c3c4 liver after 12 weeks therapy (P < 0.0005, 1 way anova). A significant reduction in mean hepatic MMTV RNA levels was seen with Truvada alone, whereas a trend for decreased viral load was observed with regimens containing Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM, *P < 0.01 vs. placebo by Dunn's multiple comparison test]. (B) Mice receiving placebo showed MMTV p27 Gag protein reactivity in biliary epithelial cells. This reactivity was attenuated in mice treated with Combivir and Kaletra. [Haematoxylin, 200× magnification with 400× in insets showing staining in biliary epithelial cells].
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fig05: Antiretroviral therapy associated with reduced hepatic MMTV RNA and biliary epithelial cell-associated MMTV Gag expression. (A) Antiretroviral therapy modulated MMTV RNA levels in the NOD.c3c4 liver after 12 weeks therapy (P < 0.0005, 1 way anova). A significant reduction in mean hepatic MMTV RNA levels was seen with Truvada alone, whereas a trend for decreased viral load was observed with regimens containing Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM, *P < 0.01 vs. placebo by Dunn's multiple comparison test]. (B) Mice receiving placebo showed MMTV p27 Gag protein reactivity in biliary epithelial cells. This reactivity was attenuated in mice treated with Combivir and Kaletra. [Haematoxylin, 200× magnification with 400× in insets showing staining in biliary epithelial cells].

Mentions: Since the combination antiretroviral therapy was found to decrease histological scores, we tested whether the antiretroviral therapy also reduced hepatic MMTV viral load through qRT-PCR 16. At the end of the study, antiretroviral therapy was found to significantly reduce hepatic MMTV RNA levels in the NOD.c3c4 mice (Fig.5A). Furthermore, treatment with Truvada led to a significant reduction in hepatic MMTV RNA compared to placebo (Fig.5A, P < 0.01), whereas, regimens based on Combivir showed no significant differences in viral burden vs. placebo. As MMTV Gag expression was previously observed in biliary epithelial cells, we tested whether this expression was affected in mice receiving combination antiretroviral therapy (Fig.5B). While Gag reactivity was readily observed in biliary epithelium of mice on placebo, mice receiving combination antiretroviral therapy were found to have reduced Gag expression in biliary epithelial cells.


Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

Sharon D, Chen M, Zhang G, Girgis S, Sis B, Graham D, McDougall C, Wasilenko ST, Montano-Loza A, Mason AL - Liver Int. (2014)

Antiretroviral therapy associated with reduced hepatic MMTV RNA and biliary epithelial cell-associated MMTV Gag expression. (A) Antiretroviral therapy modulated MMTV RNA levels in the NOD.c3c4 liver after 12 weeks therapy (P < 0.0005, 1 way anova). A significant reduction in mean hepatic MMTV RNA levels was seen with Truvada alone, whereas a trend for decreased viral load was observed with regimens containing Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM, *P < 0.01 vs. placebo by Dunn's multiple comparison test]. (B) Mice receiving placebo showed MMTV p27 Gag protein reactivity in biliary epithelial cells. This reactivity was attenuated in mice treated with Combivir and Kaletra. [Haematoxylin, 200× magnification with 400× in insets showing staining in biliary epithelial cells].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403978&req=5

fig05: Antiretroviral therapy associated with reduced hepatic MMTV RNA and biliary epithelial cell-associated MMTV Gag expression. (A) Antiretroviral therapy modulated MMTV RNA levels in the NOD.c3c4 liver after 12 weeks therapy (P < 0.0005, 1 way anova). A significant reduction in mean hepatic MMTV RNA levels was seen with Truvada alone, whereas a trend for decreased viral load was observed with regimens containing Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM, *P < 0.01 vs. placebo by Dunn's multiple comparison test]. (B) Mice receiving placebo showed MMTV p27 Gag protein reactivity in biliary epithelial cells. This reactivity was attenuated in mice treated with Combivir and Kaletra. [Haematoxylin, 200× magnification with 400× in insets showing staining in biliary epithelial cells].
Mentions: Since the combination antiretroviral therapy was found to decrease histological scores, we tested whether the antiretroviral therapy also reduced hepatic MMTV viral load through qRT-PCR 16. At the end of the study, antiretroviral therapy was found to significantly reduce hepatic MMTV RNA levels in the NOD.c3c4 mice (Fig.5A). Furthermore, treatment with Truvada led to a significant reduction in hepatic MMTV RNA compared to placebo (Fig.5A, P < 0.01), whereas, regimens based on Combivir showed no significant differences in viral burden vs. placebo. As MMTV Gag expression was previously observed in biliary epithelial cells, we tested whether this expression was affected in mice receiving combination antiretroviral therapy (Fig.5B). While Gag reactivity was readily observed in biliary epithelium of mice on placebo, mice receiving combination antiretroviral therapy were found to have reduced Gag expression in biliary epithelial cells.

Bottom Line: Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score.Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice.Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Show MeSH
Related in: MedlinePlus