HIV Hijacks Cell Sugar Coating to Hide From Immune Killers

HIV remains incurable partly because infected cells evade immune clearance through multiple mechanisms. This study reveals a novel glycan-based immune evasion strategy: HIV infection reprograms host glycosylation enzymes in CD4+ T cells to massively upregulate sialic acid-containing glycans (sialoglycans) on the cell surface — molecules that act as molecular 'don't eat me' signals by engaging inhibitory Siglec receptors on myeloid immune cells.

The researchers first mined single-cell RNA-seq data from HIV-positive and HIV-negative donors and identified Siglec-3, -7, -9, and -10 as the most abundantly expressed inhibitory Siglecs on circulating effector immune cells, particularly monocytes and NK cells. They then infected primary human CD4+ T cells with HIV and used recombinant Siglec-Fc chimeras to quantify surface ligands. HIV infection significantly increased sialoglycan ligands for Siglec-3, -7, and -9, but not Siglec-10. Critically, this effect was driven by HIV itself — not merely T cell activation — and was confirmed with both activated and non-activated CD4+ T cells infected with two different HIV strains.

Using CRISPR-Cas9 gene editing and targeted glycomic profiling (including lectin arrays and mass spectrometry), the team identified specific upregulated sialylated glycan species — particularly α2-3 and α2-6 sialylated N- and O-glycans — and pinpointed the glycosyltransferase enzymes responsible, including ST3GAL4 and ST6GAL1. HIV viral protein expression, rather than innate immune activation alone, was shown to drive these glycan changes.

Functionally, these sialoglycans suppressed monocyte and neutrophil cytotoxic activity against HIV-infected cells. The team then engineered 10-1074-SiaD, conjugating the broadly neutralizing anti-HIV antibody 10-1074 to a sialidase enzyme. This targeted construct selectively stripped sialic acids from HIV-infected cells (not uninfected bystanders), significantly enhancing myeloid cell-mediated killing in autologous ex vivo assays. In humanized female mice with HIV infection, 10-1074-SiaD treatment reduced viral loads and systemic inflammation markers compared to controls.

These findings establish the sialoglycan-Siglec axis as a bona fide HIV immune evasion mechanism and provide proof-of-concept for targeted glycan-editing immunotherapies. This approach complements existing HIV cure strategies focused on viral latency reversal or T cell-based immunity.