Hypercholesterolemia exacerbates virus-induced immunopathologic liver disease via suppression of antiviral cytotoxic T cell responses

The immune system has to be optimally balanced to be highly effective again st infections with cytopathic microbial pathogens and must guarantee effici ent destruction of cells infected with noncytopathic agents while leaving t he integrity of noninfected cells largely unaltered. We describe here the e ffects of genetically induced hypercholesterolemia on cellular immunity in apolipoprotein E (ApoE(-/-)) and low density lipoprotein receptor-deficient (LDLR-/-) mice during infection with the hepatotropic lymphocytic choriome ningitis virus WE strain. In both ApoE(-/-) and LDLR-/- mice hypercholester olemia aggravated virus-induced immunopathologic liver disease. ApoE(-/-) m ice exhibited a higher susceptibility to virus-induced immunopathology than LDLR-/- mice and usually succumbed to immunopathologic disease when infect ed with high doses of virus. Initial virus spread was not influenced by the hypercholesterolemia, whereas clearance of the virus from spleen and nonly mphoid organs, including liver, was delayed. Activation of antiviral CTL, m easured by ex vivo cytotoxicity and LFN-gamma production, and recruitment o f specific CTL into blood and liver were impaired in hypercholesterolemic m ice, indicating that hypercholesterolemia had a significant suppressive eff ect on cellular immunity. Taken together, these data provide evidence that hypercholesterolemia suppresses antiviral immune responses, thereby changin g the host-virus balance, and can increase susceptibility to acute or chron ic and potentially lethal virus-induced immunopathologic disease. These fin dings impinge on our understanding of hypercholesterolemia as a disease par ameter and may explain aspects of the frequent association of persistent pa thogens with hypercholesterolemia-induced diseases, such as atherosclerosis .