The Host Cell Sulfonation Pathway Contributes to Retroviral Infection at a Step Coincident with Provirus Establishment

来自 EBSCO

阅读量：

作者：

JW Bruce，P Ahlquist，JAT Young，PD Bieniasz

展开

摘要：

The early steps of retrovirus replication leading up to provirus establishment are highly dependent on cellular processes and represent a time when the virus is particularly vulnerable to antivirals and host defense mechanisms. However, the roles played by cellular factors are only partially understood. To identify cellular processes that participate in these critical steps, we employed a high volume screening of insertionally mutagenized somatic cells using a murine leukemia virus (MLV) vector. This approach identified a role for 3′-phosphoadenosine 5′-phosphosulfate synthase 1 (PAPSS1), one of two enzymes that synthesize PAPS, the high energy sulfate donor used in all sulfonation reactions catalyzed by cellular sulfotransferases. The role of the cellular sulfonation pathway was confirmed using chemical inhibitors of PAPS synthases and cellular sulfotransferases. The requirement for sulfonation was mapped to a stage during or shortly after MLV provirus establishment and influenced subsequent gene expression from the viral long terminal repeat (LTR) promoter. Infection of cells by an HIV vector was also shown to be highly dependent on the cellular sulfonation pathway. These studies have uncovered a heretofore unknown regulatory step of retroviral replication, have defined a new biological function for sulfonation in nuclear gene expression, and provide a potentially valuable new target for HIV/AIDS therapy. A genetic screen was used to identify host cell functions important for the replication of retroviruses, including human immunodeficiency viruses. These studies have uncovered a heretofore unexpected role for the cellular sulfonation pathway in an intracellular step of retroviral replication. Through the addition of sulfate groups, this pathway is responsible for modifying and regulating different types of cellular factors including proteins, lipids, carbohydrates and hormones. The role of this pathway was further confirmed by using specific chemical inhibitors. The sulfonation requirement was mapped to a step during viral DNA integration into the host genome that has a subsequent effect upon the level of expression of viral genes. These studies have uncovered a new regulatory mechanism of retroviral replication and suggest that components of the host cell sulfonation pathway might represent attractive targets for antiviral development.

展开

关键词：

Animals Humans Proviruses Cell Line Leukemia Virus, Murine Sulfates Sulfate Adenylyltransferase Transfection Virus Replication Genetic Vectors