Cellular Cholesterol Homeostasis and HIV: Identifying New Players In Virus Replication

Abstract

The assembly and release of retroviruses involve a highly orchestrated and controlled series of interactions between viral and host cell proteins. Previous work in our laboratory and others indicate that cholesterol-rich regions of cell membranes called lipid rafts play an important role in this process. Additional studies have strongly implicated cholesterol as a key lipid in the entry and egress of HIV from cells. We have examined the role of a key protein involved in cellular cholesterol homeostasis, NPC-1, in the biology of HIV-1. Defects in the expression and or function of this protein in vivo have been shown to be associated with a rare disorder, Niemann Pick Type C disease, characterized by accumulation of cholesterol and sphingolipids in large intracellular membranous structures. The protein NPC-1 appears to be critical for the normal trafficking of cholesterol between intracellular and plasma membrane pools. Our results show that HIV-1 release from infected cells lacking expression of functional NPC-1 is severely impaired. Chemical induction of the NPC disease phenotype in normal HIV-infected cells resulted in drastically reduced HIV-1 release. Our data indicate for the first time that a protein associated with cholesterol trafficking is required for HIV release. These studies may provide the basis for the identification of novel therapeutic strategies.