Unexpectedly, we found that bystander cells within HIV-infected cultures also responded to HIV infection by upregulating a subset of these antiviral genes, including ISG15, LY96, IFI6, and IFITM3. Moreover, we found that upregulation of these factors was reduced in bystander cells from Vpr-positive versus Vpr-negative HIV-infected primary macrophage cultures. Here, IFI6 is linked to HIV infectious disease.