Postdoctoral Position in Virology

Virginia Commonwealth University
Richmond, Virginia
Located in Richmond, Virginia (RVA), we have close proximity to Washington DC, Atlantic beaches etc
May 08 2019
Position Type
Full Time
Organization Type

Postdoctoral Position in Virology

One post-doctoral position is available at Virginia Commonwealth University to investigate Epstein-Barr virus (EBV)-host cell interactions.

Epstein-Barr virus (EBV), best known for causing infectious mononucleosis (also called “mono” or "kissing disease"), is the causative agent of nasopharyngeal cancer (a type of head and neck cancer), stomach cancer and several types of lymphomas. Each year 200,000 cancers worldwide are caused by EBV. The presence of EBV in cancer cells also provides a unique opportunity for targeted therapy by forcing tumor cells to reactivate latent EBV. The Li lab is focusing on understanding the molecular mechanisms by which viral and host factors control the transition of EBV from latency to reactivation with a goal of developing novel therapeutic strategies to cure EBV-associated cancer. Current projects in our lab include:

Project 1. Conserved herpesvirus protein kinases (CHPKs) regulation of host protein phosphorylation. 

Herpesviruses each encode a conserved protein kinase, CHPK, that is conserved throughout all subfamilies of Herpesviridae. Like cellular protein kinases that regulate many aspects of cell biology, CHPKs regulate multiple vital steps in the viral life cycle, including primary infection, lytic replication and nuclear egress. My previous study at the Hayward lab (Johns Hopkins University) identified more than 100 shared CHPKs targets using a high throughput screening approach based on human protein microarrays. Further studies demonstrated that CHPKs, including EBV protein kinase BGLF4, actively induce a host DDR via TIP60 phosphorylation to foster viral replication (Li et al, Cell Host & Microbe, 2011). More recently, we utilized stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics and discovered more than 1,000 direct/indirect cellular targets for EBV protein kinase BGLF4. Functional analyses revealed significant enrichment of pathways related to the DNA damage response (DDR), mitosis and cell cycle (Li et al, PLOS Pathogens, 2015). Based on these findings, our lab is investigating one potential key BGLF4 target, sterile alpha motif and HD domain 1 (SAMHD1), in EBV lytic replication. SAMHD1 was recently identified as an intrinsic restriction factor for a variety of viruses. Aside from human immunodeficiency virus 2 (HIV-2) and the related simian immunodeficiency virus (SIV) Vpx proteins, the direct viral countermeasures against SAMHD1 restriction remain unknown. Using EBV as a primary model, we discovered that SAMHD1-mediated anti-viral restriction is antagonized by EBV BGLF4. Mechanistically, we found that BGLF4 phosphorylates SAMHD1 and thereby inhibits its dNTPase activity. We further demonstrated that the targeting of SAMHD1 for phosphorylation is a common feature shared by beta- and gamma-herpesviruses. Together, our findings uncover a unique immune evasion mechanism whereby herpesviruses exploit the phosphorylation of SAMHD1 to thwart host defenses (Zhang et al, Cell Report 2019, Accepted).

Project 2. Host restriction factors control of EBV reactivation.

Our lab recently discovered PIAS1 (protein inhibitor of activated STAT1) as a new EBV restriction factor. PIAS1 has been implicated in several cellular functions, including transcriptional regulation, inhibition of inflammation response and involvement in DNA damage response. Initially, PIAS1 was found in association with an EBV protein kinase BGLF4 by our proteomics study (Li et al, PLOS Pathogens, 2015), which prompted us to explore its potential role in EBV life cycle. Using a CRISPR/Cas9 genomic editing approach, we demonstrated that PIAS1 depletion significantly facilitates EBV reactivation, while PIAS1-reconstitution had the opposite effect. Caspase activation was observed in EBV-positive cells following lytic induction. Remarkably, we found that caspase-dependent cleavage of PIAS1 antagonizes PIAS1-mediated restriction toward EBV, and that caspase inhibition suppresses EBV replication through blocking PIAS1 cleavage. We further demonstrated that a cleavage-resistant PIAS1 mutant suppresses EBV replication upon lytic induction (Zhang et al, Cell Reports, 2017Lv et al, Omics, 2017). In a parallel study, we demonstrated that interferon regulatory factor 8 (IRF8) regulates EBV reactivation through promoting caspases expression and hence their activation upon lytic induction, which leads to the de-stabilization of several host factors suppressing lytic replication, including KAP1 (Lv et al, PLOS Pathogens, 2018).

Ongoing research will elucidate how PIAS1 restricts EBV replication, determine how KAP1 is regulated by caspases, and discover new EBV restriction factors that are antagonized by caspases. We are also interested in investigating how different restriction factors coordinate to limit viral replication and how viruses utilize cellular caspases or viral protein kinases to antagonize their restriction.

Applicants should have a recent Doctoral Degree (or soon to graduate)  in the areas of virology, molecular biology and/or immunology, and have published first author papers.

Competitive salary will be commensurate with experience (NIH recommended salary for postdocs). Interested applicants should submit a single PDF file consisting of a CV, a brief description of their research achievements and interests, and names of at least three referees to Dr. Li ( Candidate will be considered until the position is filled.