Identification of Interferon-Stimulated Genes with Antiretroviral Activity

Interferons (IFNs) exert their anti-viral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). The activity of known ISGs is insufficient to account for the antiretroviral effects of IFN, suggesting that ISGs with antiretroviral activity are yet to be described. We constructed an arrayed library of ISGs from rhesus macaques and tested the ability of hundreds of individual macaque and human ISGs to inhibit early and late replication steps for 11 members of the retroviridae from various host species. These screens uncovered numerous ISGs with antiretroviral activity at both the early and late stages of virus replication. Detailed analyses of two antiretroviral ISGs indicate that indoleamine 2,3-dioxygenase 1 (IDO1) can inhibit retroviral replication by metabolite depletion while tripartite motif-56 (TRIM56) accentuates ISG induction by IFNα and inhibits the expression of late HIV-1 genes. Overall, these studies reveal numerous host proteins that mediate the antiretroviral activity of IFNs. [Display omitted] •ISG screening identifies direct and indirect antiretroviral proteins•Interferon-γ inhibits HIV-1 through IDO1-mediated tryptophan depletion•TRIM56 enhances the antiretroviral potential of interferon-α Screening of interferon-stimulated genes for antiretroviral activity reveals numerous genes that directly or indirectly inhibit retroviral replication. Detailed analyses of two antiretroviral effectors indicate that IDO1 inhibits retroviral replication via nutrient depletion while TRIM56 increases the antiretroviral potential of IFNα.