Furthermore, it is known that the human ortholog of SID-3, activated CDC42-associated kinase (ACK1/TNK2), is capable of phosphorylating human WASP, suggesting that VIRO-2 may be a substrate for SID-3 in <i>C. elegans</i> A targeted RNA interference (RNAi) knockdown screen further identified the <i>C. elegans</i> gene <i>nck-1</i>, which has a human ortholog that interacts with TNK2 and WASP, as required for Orsay virus infection.Thus, genetic screening in <i>C. elegans</i> identified critical roles in virus infection for evolutionarily conserved genes in a known human pathway.<b>IMPORTANCE</b> Orsay virus is the only known virus capable of naturally infecting the model organism <i>Caenorhabditis elegans</i>, which shares many evolutionarily conserved genes with humans.