Restriction of Lentiviruses by SAMHD1

点击翻译按钮获取中文摘要

Humans have evolved host restriction factors that prevent the replication of the human immunodeficiency virus (HIV) and other retroviruses. Unfortunately, viruses have managed to circumvent these restrictions. One mechanism by which retroviruses such as HIV counteract host cell restrictions is by encoding accessory protein such as Vpx, a virion-packaged virus protein that counteracts the host restriction factor SAMHD1, inducing its proteasomal degradation. SAMHD1 blocks the replication of retroviruses in macrophages and dendritic cells, cell-types that play an important role in the adaptive and innate immune response and are a key target of lentiviruses. SAMHD1 is a phosphohydrolase that destroys the cells deoxynucleoside triphosphates (dNTP). Because dNTPs are the building blocks for DNA, they are required by viruses to replicate their genome following entry into a target cell. Thus, depletion of the dNTP pool by SAMHD1 protects the cell from becoming infected. Vpx is packaged in the virus and is released upon entry. Upon release, Vpx interacts with SAMHD1 and directs it to the proteasomal degradation pathway. The project will investigate the mechanism by which Vpx destroys SAMHD1 and how the enzymatic activity and amount of SAMHD1 is controlled by the cell. To do this, cellular proteins that interact with SAMHD1 will be identified and post-translational modifications of the protein will be characterized. Understanding the regulation of SAMHD1 in different cell-types will provide novel strategies to limit the replication of HIV-1 and to improve the effectiveness of the host immune response to the virus.