Several cell-intrinsic effectors drive type I interferon-mediated restriction of HIV-1 in primary CD4+T cells

Type I interferon (IFN) upregulates proteins that inhibit HIV within infected cells. Prior studies have identified IFN-stimulated genes (ISGs) that impede lab-adapted HIV in cell lines, yet the ISG(s) that mediate IFN restric-tion in HIV target cells, primary CD4+T cells, are unknown. Here, we interrogate ISG restriction of primary HIV in CD4+ T cells by performing CRISPR-knockout screens with a custom library that specifically targets ISGs expressed in CD4+ T cells. Our investigation identifies previously undescribed HIV-restricting ISGs (HM13, IGFBP2, LAP3) and finds that two factors characterized in other HIV infection models (IFI16 and UBE2L6) mediate IFN restriction in T cells. Inactivation of these five ISGs in combination further diminishes IFN's pro-tective effect against diverse HIV strains. This work demonstrates that IFN restriction of HIV is multifaceted, resulting from several effectors functioning collectively, and establishes a primary cell ISG screening model to identify both single and combinations of HIV-restricting ISGs.

Automated summary

This study identifies new ISGs that inhibit HIV and confirms the role of certain factors in IFN restriction in T cells. The findings demonstrate the multifaceted nature of IFN restriction against HIV and establish a screening model for identifying HIV-restricting ISGs.