ABSTRACT
Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small alpha, prebeta-1, and other prebeta forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Prebeta-1-like HDL had a plasma residence time of 8 +/- 6 h and was converted entirely to large alpha-HDL having residence times of 13-14 h. Small alpha-HDL was converted entirely to large alpha-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis.
Subject(s)
Cholesterol/metabolism , Lipid Metabolism , Lipoproteins, LDL , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Aorta/pathology , Apolipoprotein A-I/metabolism , Atherosclerosis/pathology , Atherosclerosis/physiopathology , Biological Transport , Cell Line , Chlorocebus aethiops , Humans , Lipoproteins, HDL/metabolism , Lipoproteins, LDL/blood , Lipoproteins, LDL/chemistry , Mice , Scavenger Receptors, Class B/metabolismABSTRACT
This pilot experiment in a simian immunodeficiency virus (SIV) chronic infection model aimed at extending our previous findings that vaccination with delipidated SIV resulted in more potent and diversified antiviral responses (1). Macaques chronically infected with SIVmac239 treated with antiretroviral therapy (ART) were vaccinated with autologous delipidated virus via consecutive lymph node targeted immunizations-1, 1 and 10 mug of virus spaced monthly. Results showed all animals had lasting viral load reduction approaching 1 log compared to set-point, and disease delay. Delipidation may enhance processing/ presentation of viral antigen eliciting potent antiviral control even at such late infection stage.
Subject(s)
Retroviridae/metabolism , SAIDS Vaccines/chemistry , Animals , Antibodies/chemistry , Antigens, Viral/chemistry , Antiviral Agents/pharmacology , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/metabolism , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Macaca mulatta , Pilot Projects , Time FactorsABSTRACT
We tested the hypothesis that removal of viral lipids using diisopropylether can enhance antigenicity of SIVmac251. DIPE delipidation removed cholesterol from SIVmac251 without significant loss of viral protein or RNA. Mice immunized with the same SIV preparation but boosted with delipidated SIVmac251 exhibited significantly broader and higher cellular and humoral immune responses compared to live or AT-2-inactivated virus. As little as 1microg (total protein) of delipidated virus was sufficient to induce such enhanced immune responses. Thus, solvent treated lentivirus may provide a novel strategy to generate immune responses to additional viral epitopes.