Host cell glycosylation selects for infection with CCR5- versus CXCR4-tropic HIV-1

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection involves a selection bottleneck that leads to transmission of one or a few variants. C–C motif chemokine receptor 5 (CCR5) or C–X–C motif chemokine receptor 4 (CXCR4) can act as coreceptors for HIV-1 viral entry. However, initial infection mostly occurs via CCR5, despite abundant expression of CXCR4 on target cells. The host factors that influence HIV-1 susceptibility and selection during transmission are unclear. Here we conduct CRISPR–Cas9 screens and identify SLC35A2 (a transporter of UDP–galactose expressed in target cells in blood and mucosa) as a potent and specific CXCR4-tropic restriction factor in primary target CD4+ T cells. SLC35A2 inactivation, which resulted in truncated glycans, not only increased CXCR4-tropic infection levels but also decreased those of CCR5-tropic strains consistently. Single-cycle infections demonstrated that the effect is cell-intrinsic. These data support a role for a host protein that influences glycan structure in regulating HIV-1 infection. Host cell glycosylation may, therefore, affect HIV-1 selection during transmission in vivo. CRISPR–Cas9 screens in primary CD4+ T cells enable identification of SLC35A2 as a host factor that restricts CXCR4-tropic HIV-1 viral entry and promotes that of CCR5-tropic viruses.