Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY The HIV-1 Vif protein is expressed late during infection and has a well-described function to ubiquitinate and degrade proteins in the APOBEC3 family, thus neutralizing their antiviral activities. More recently, an additional function of HIV-1 Vif was described by us and others to ubiquitinate and degrade protein phosphatase 2A holoenzymes containing B56 family regulatory subunits (PP2A-B56). The conservation of Vif-mediated PP2A- B56 degradation throughout globally circulating HIV-1 subtypes suggests that it is functionally important. However, there remains a gap in understanding the mechanisms by which PP2A-B56 degradation confers a fitness advantage to HIV-1. Furthermore, in contrast to APOBEC3 degradation, the host cellular determinants required for Vif-mediated ubiquitination and degradation of PP2A-B56 are undefined. In this project, we aim to address these gaps in understanding by defining the cellular determinants and functional effects of PP2A-B56 degradation by HIV-1 Vif. In Aim 1, we will apply unbiased protein interaction technologies to determine proteins interacting with PP2A-B56 while it is degraded by Vif. In Aim 2, we will carry out a genome- wide CRISPR/Cas9 genetic screen to identify genes regulating APOBEC3 and PP2A-B56 degradation. In Aim 3, will test the impact of individual phosphorylation sites regulated by PP2A-B56 in HIV-1 replication in primary CD4+ T cells. Successful completion of this project will advance understanding of the Vif-PP2A-B56 signaling axis, potentially leading towards the development of novel classes of antiretroviral therapies that target late processes of HIV-1 infection.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
