HIV-induced sialoglycans on infected CD4+ T cells promote immune evasion from myeloid cell-mediated killing

Sialic acid-containing glycans (sialoglycans) on pathological cells interact with Siglecs, glyco-immune checkpoint receptors expressed on myeloid cells, suppressing the cytotoxic functions of these immune cells. Using targeted glycomic analyses and gene editing, we show that HIV infection reprograms the glycosylation machinery of infected cells to increase the expression of the sialoglycan ligands for Siglec-3, -7, and -9. These ligands engage Siglecs on myeloid cells, impairing their ability to target HIV-infected cells. Selective disruption of these interactions using 10-1074-SiaD, an HIV-specific antibody conjugated to sialidase, an enzyme that removes sialic acids, significantly enhances monocyte- and neutrophil-mediated killing of HIV-infected cells in autologous assays. Treatment with 10-1074-SiaD in female humanized mice infected with HIV reduces viral load and decreases inflammation. These findings reveal an immune evasion mechanism exploited by HIV to evade myeloid cell immune surveillance and highlight the potential of targeting sialoglycan-Siglec interactions to improve immune clearance of HIV-infected cells.