The work presented here shows that the latency-associated upregulation of HCLS1, which we previously identified in an unbiased analysis of changes in the cell proteome upon HCMV latent infection (Elder et al., 2019), modulates cell motility of latently infected cells and increases their ability to extravasate across endothelial cell layers. This evidence concerns the gene HCLS1 and disease arising from reactivation of latent virus.