Disruption of CPSF6 enhances cellular permissivity to HIV-1 infection through alternative polyadenylation

Human immunodeficiency virus (HIV) relies upon a broad array of host factors in order to replicate and evade the host antiviral response¹. Cleavage and polyadenylation specificity factor 6 (CPSF6) is one such host factor that is recruited by incoming HIV-1 cores to regulate trafficking², nuclear import^3-5, uncoating⁶, and integration site selection^4,6-11. Despite these well-described roles, the impact of CPSF6 perturbation on HIV-1 infectivity varies considerably by cell type. Here, we report that CPSF6 knock-out in primary CD4+ T cells leads to increased permissivity to HIV-1 infection due to broad transcriptional reprogramming. Knock-out of CPSF6 results in widespread differential gene expression, including downregulation of genes involved in the innate immune response and enhanced expression of the HIV-1 co-receptors. Accordingly, these cells are less responsive to interferon and express lower levels of antiretroviral restriction factors, including TRIM5α. These transcriptional changes are linked to global shortening of mRNA 3' untranslated regions (UTRs) through alternative polyadenylation (APA), which is triggered by disruption of the CPSF6-containing Cleavage Factor Im (CFIm) complex^12,13. Furthermore, we find that recruitment of CPSF6 by HIV-1 cores is sufficient to perturb CPSF6 function, leading to 3' UTR shortening and subsequent transcriptional rewiring. These results suggest a novel mechanism by which HIV-1 transcriptionally reprograms CD4+ T cells through recruitment of CPSF6 to circumvent the innate immune response and enhance permissivity to infection.