Immune Evasion Uncovered by Virome-Wide Ubiquitin Ligase Discovery

In a new study published in Science titled, “Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion,” researchers from Harvard Medical School (HMS) have uncovered how viruses hijack cells’ garbage-disposal systems to evade immune attack. 

The study applies ORFeome, a tool that broadens the scale by which researchers study viral proteins. The advance proposes to speed basic discoveries in virology, inform the development of new vaccines and treatments to protect against emerging pathogens. 

“This library reveals how viruses manipulate human cells on a scale that simply wasn’t possible before,” said Stephen Elledge, PhD, professor of genetics and medicine at Harvard Medical School and senior author of the study. “We believe it changes virology from studying one virus at a time to discovering the common strategies and surprising innovations that viruses have evolved, providing a powerful new foundation for understanding emerging viral threats.” 

ORFeome and other ORF libraries are named after open reading frames, DNA sequences that encode proteins. Previous viral ORF libraries from other groups focused on individual viruses or virus families that contained 100 or 200 sequences each. The new ORFeome contains about 13,000 physical DNA sequences, or constructs, that code for about 9,000 proteins from 513 different viruses, including Andes hantavirus, Ebola virus, and Zika virus. 

“Most viruses have never been studied in detail, yet evolution has already performed countless experiments for us. This library gives us a way to read the results of those experiments across the viral world,” said Elledge, who is also a Howard Hughes Medical Institute (HHMI) Investigator. 

The team attached a genetic barcode to each ORF, allowing researchers to conduct studies of all 13,000 ORFs at once. 

“We can insert the sequences into a population of cells, ask questions like which ones cause the cells to grow better or less, and then identify those by their barcodes when the experiment is finished,” said Colin O’Leary, PhD, HMS research fellow and co-author on the study. “It hasn’t been possible before to do genetic screens like this with viral proteins.” 

The team will make the ORFeome freely available for the research community. Elledge and colleagues implemented a flexible design to enable application to other model systems and experiments. 

The team conducted genetic screens in three cell types, searching for viral proteins that affect cell proliferation, stop cells from presenting antigens to trigger the immune system to attack, or block the effects of interferon. Results uncovered more than 700 viral proteins that contribute to at least one of those actions. 

The study opens opportunities to design drugs that hinder viral activity while sparing normal function.