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

• Published in: Nature microbiology Vol. 9; no. 11; pp. 2985 - 2996
• Main Authors: Itell, Hannah L., Guenthoer, Jamie, Humes, Daryl, Baumgarten, Nell E., Overbaugh, Julie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.10.2024; Nature Publishing Group
• Subjects: 13/106; 13/31; 38/1; 38/44; 38/77; 42/40; 42/41; 45/23; 631/326/596/1787; 631/326/596/2556; 631/326/596/2557; 631/326/596/2563; 631/80/221; Biomedical and Life Sciences; CC chemokine receptors; CD4 antigen; Chemokine receptors; Chemokines; CRISPR; CXCR4 protein; Disease transmission; Galactose; Glycosylation; HIV; Human immunodeficiency virus; Infections; Infectious Diseases; Life Sciences; Lymphocytes T; Medical Microbiology; Microbiology; Parasitology; Polysaccharides; Protein structure; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-024-01806-7

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.