FXR and Anti-HIV Therapy Figure 4. FXR and PPAR a ligands protects against aortic plaques formation induced by the HIV-PI ritonavir to ApoE2/2 mice. Panel A. Administration of ritonavir (5 mg/kg/day) to ApoE2/2 for 12 weeks increases the size of aortic plaques expressed of ratio of plaque surface area to vessel surface area. The effect was significantly attenuated by co-treating mice with gemfibrozil or CDCA. Individual data of 10 animals per group are shown. *P,0.05 versus wild type naive; #P,0.05 treatments versus ritonavir. Panel B. Pseudo-colour representation of aortic plaques from individual animals. The images show the plaque surface from individual animals, each one representative of a specific experimental group. The lipids in the vessel wall were staining with Sudan IV, as described in Material and Methods, and shown in red. Panel C–H. Plasmatic levels of ALT, triacylglycerols, cholesterol, HDL, LDL and glucose in ApoE2/2 mice. ApoE2/2 mice show increased plasma cholesterol, triacylglycerols and LDL plasma levels and decreased HDL plasma levels in comparison to their wild-type counterparts (n = 10; * P,0.01 versus naive wild type). Twelve-weeks administration of ritonavir failed to change this pattern and pharmacological treatments were unable to attenuate the pro-atherogenetic lipid profile observed in ApoE2/2 administered ritonavir (n = 10). doi:10.1371/journal.pone.0013238.g004 demonstrated effective in reducing dyslipidemia in clinical settings [21,22]. FXR activation protects against development of dyslipidemia in wild type mice HAART has had a dramatic effect in reducing morbidity and mortality associated with HIV-1 infection. However, concern has been raised in relation to the increased risk of coronary heart disease linked to chronic use of HAART. Findings from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study indicate that the incidence of myocardial infarction in HIV infected persons increases with long-term exposure to HAART [2–4,8]. In a large prospective observational study including 23,437 patients the incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to HIV PIs to 6.01 per 1000 person-years in those exposed to HIV PIs for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of HIV PIs exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23). Despite adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18), these results demonstrate that exposure to protease inhibitors is associated with an increased risk of myocardial infarction which is only partly explained by dyslipidemia. In contrast, there is no evidence that the use of non-nucleoside reverse-transcriptase PLoS ONE | www.plosone.org 6 October 2010 | Volume 5 | Issue 10 | e13238