# Targeting Siglec-9/Sialoglycan Interactions to Enhance NK Functions During HIV Infection

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $408,072

## Abstract

PROJECT SUMMARY: The functions of Natural Killer (NK) cells can be influenced by the cell-surface
glycosylation of their target cells. A subset of CD56dim NK cells expresses the Sialic acid-binding protein Siglec-
9. This subset has a high cytolytic activity; however, Siglec-9 itself is an inhibitory receptor that restrains the
cytolytic ability of this otherwise highly cytotoxic population. Harnessing the cytotoxic capacity of this population
has not been evaluated as an approach for eradicating HIV. In our preliminary studies and focusing first on NK
cells, we found that levels of Siglec-9+ CD56dim NK cells inversely correlate with CD4+ T cell-associated HIV DNA
during antiretroviral therapy (ART)-suppressed HIV infection. Furthermore, Siglec-9+ CD56dim NK cells exhibited
higher cytotoxicity towards HIV+ cells compared to Siglec-9- NK cells. These data are consistent with the highly
cytotoxic nature of the Siglec-9+ NK cells. However, consistent with the known inhibitory function of the Siglec-9
molecule itself, blocking Siglec-9 enhanced NK cells' ability to kill HIV+ cells in vitro. Focusing next on target
cells, we found that HIV latently-infected CD4+ T cells exhibit high levels of the Siglec-9 ligand, α2-3 Sialic acid,
compared to HIV productively-infected or uninfected cells. We also developed a novel approach to block
Siglec/Sialic acid interactions during HIV infection by conjugating Sialidase (enzyme cleaves Sialic acid) to four
HIV broadly neutralizing antibodies (bNAbs). These conjugates (in hand) can be used in conjunction with drugs
that reactivate HIV latently-infected cells to achieve a functional HIV cure. We pilot tested one of these conjugates
and found it able to selectively desialylate the surface of HIV+ cells and enhance NK capacity to kill these infected
cells in vitro. Together, our data support our central hypothesis that Siglec/sialoglycan interactions contribute
to the ability of HIV-infected cells to evade NK immune surveillance and that blocking these interactions, via
selective desialylation of HIV-infected cells, will enhance the capacity of NK cells to clear HIV-infected cells.
 In Aim 1: we will test the hypothesis that Siglec-9/Sialic acid interactions contribute to the ability of HIV
latently-infected cells to evade NK immune surveillance. In (1a), we will determine the role of Siglec-9 in the
ability of NK cells to kill HIV+ cells, and in (1b), we will determine the role of α2-3 Sialic acid in the ability of HIV
latently-infected CD4+ T cells to evade killing by NK cells. In Aim 2: we will test the hypothesis that HIV bNAb-
Sialidase conjugates reduce the size of the HIV reservoir (2a) in vitro and (2b) ex vivo, and (2c) delay viral
rebound in vivo using a modified version of the splenic-injected primary HIV-infected reservoir (SPHIR-IL15)
non-fetal humanized mouse model with high NK longevity. We also will confirm the mechanism by which bNAb-
Sialidase conjugates enhance NK cell antiviral function by examini...

## Key facts

- **NIH application ID:** 11229103
- **Project number:** 7R01AI165079-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mohamed Abdel Mohsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,072
- **Award type:** 7
- **Project period:** 2021-06-25 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11229103

## Citation

> US National Institutes of Health, RePORTER application 11229103, Targeting Siglec-9/Sialoglycan Interactions to Enhance NK Functions During HIV Infection (7R01AI165079-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11229103. Licensed CC0.

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