This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.3-hydroxy-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or 'statins', are competitive inhibitors of the rate-limiting step of cellular cholesterol synthesis and are commonly used to treat patients with hypercholesterolemia. In addition to their well-defined lipid-lowering properties, recent reports suggest that statins also have anti-inflammatory and immunomodulating effects independent of their ability to lower plasma cholesterol levels. The ability of statins to inhibit the inflammatory response of both monocytes and endothelial cells while possessing additional properties that are neuroprotective raised the question as to whether this class of drugs might also be beneficial in treating CNS inflammatory conditions such as HIV encephalitis (HIVE). We hypothesized that statin therapy will interfere with the trafficking of SIV-infected cells into the CNS by inhibiting the activation of microvascular brain endothelial cells and/or peripheral blood monocytes. Five adult rhesus macaques were evaluated in the current study. Three animals were treated orally with lovastatin (1mg/kg) for one week prior to intravenous inoculation with SIVmac251. Two animals were similarly inoculated with SIV; however, these animals did not receive lovastatin treatment prior to SIV infection and served as vehicle (PBS) controls. All animals were euthanized at 14 days postinoculation (dpi) concurrent with peak viremia, CNS activation, and viral neuroinvasion. Short-term lovastatin treatment failed to provide any neuroprotective effect. Evaluation of brain sections using immunohistochemistry showed evidence of widespread microglial and endothelial cell activation in the CNS of control and statin-treated infected animals. Evaluation of the gastrointestinal tract showed pronounced B-cell lymphoid hyperplasia in the small intestine of one statin-treated, SIV-infected animal. Quantitative analysis of neuron numbers in myenteric ganglia revealed a protective effect of statin therapy on ileal neurons in two of three statin-treated animals. Further assessment of viral loads and cytokine expression in this group of animals is planned.
Showing the most recent 10 out of 352 publications
