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

靶向 Siglec-9/Sialoglycan 相互作用以增强 HIV 感染期间的 NK 功能

基本信息

批准号：
10326726
负责人：
Mohamed Abdel Mohsen
金额：
$ 61.68万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-25 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326726
关键词：
Antibodies Antiviral Agents Autologous Binding Binding Proteins Blocking Antibodies Blood Breast Cancer Cell Breast Cancer Model CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Carbohydrates Cell model Cell surface Cells Chromium Cleaved cell DNA Data Enzymes Exhibits FCGR3B gene Goals HIV HIV Infections Hand Human Immune Immunologic Surveillance Immunology In Vitro Individual Interleukin-15 Leukocytes Ligands Longevity Malignant Neoplasms Mediating Mutate Natural Killer Cells Nature Neuraminidase Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Polysaccharides Population RNA Role Sialic Acids Spleen Surface T-Lymphocyte Testing Time Trastuzumab Viral antiretroviral therapy cancer cell carbohydrate binding protein cytotoxic cytotoxicity glycosylation humanized mouse immune checkpoint in vivo interdisciplinary approach mouse model neutralizing antibody novel novel strategies perforin prevent programmed cell death protein 1 receptor sialic acid binding Ig-like lectin tumor viral rebound

项目摘要

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 examining the role of Fc-mediated functions and Siglec-binding in NK targeting. Our interdisciplinary approach is taking advantage of recent advances in the emerging field of glyco-immunology to enhance NK cell capacity to kill HIV+ cells in ART-suppressed individuals. Our goal is to provide a novel mechanism and approach that can be harnessed to functionally cure HIV infection.

自然杀伤细胞（NK）的功能受细胞表面的影响