# Role of Siglec-1 in HIV Interactions with Microglia and Astrocytes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $495,301

## Abstract

Project Summary
HIV-associated neurocognitive disorders (HAND) represent a spectrum of disorders that cause significant
morbidity in persons living with HIV (PLWH). While the prevalence of HIV-associated dementia has
significantly decreased since the introduction of antiretroviral therapy (ART), milder forms of HAND are quite
common among individuals on ART. The molecular, cellular, and viral contributions to the pathogenesis of
HAND remain incompletely understood. HIV readily infects microglia of the central nervous system (CNS), and
there is evidence from animal models that microglial infection occurs within days of acute infection. Microglia
are mobile and frequently interact with other cells within the CNS, potentially mediating transmission of HIV to
uninfected cells. Recent advances in cerebral organoid development provide a means of dissecting virus-cell
and cell-cell interactions in the CNS that may be relevant to the development of HAND, including mechanisms
of cell-cell transmission of virus. Our laboratory has been studying iPSC-derived microglia in order to define
how HIV attaches to and infects this cell type. Siglec-1 is an interferon (IFN)-inducible molecule that attaches
to gangliosides on the HIV-1 lipid bilayer, leading to subsequent internalization and formation of the virus-
containing compartment (VCC) in monocyte-derived macrophages and facilitating transmission of virus to T
cells. In this project, we will define the role of Siglec-1 in mediating HIV interactions with iPSC-derived
microglia, including its role in infection of microglia and trans-infection to uninfected microglia, T cells,
macrophages, and potentially to astrocytes. Novel SIGLEC1 knockout iPSC lines will be utilized to provide new
insights into Siglec-1 in CNS infection and inflammation. Experiments will then be extended to cerebral
organoid models, and the contribution of microglial capture of HIV and microglial infection to cerebral
inflammation assessed in both 2D and 3D organoids. The effects of fentanyl exposure of HIV-infected
microglia and organoids will be analyzed, and may alter IFN signaling and the dynamics of HIV spread and
inflammation in CNS tissues. Together, these studies will provide new insights into the pathogenesis of HAND,
and identify novel therapeutic targets for this important group of disorders.

## Key facts

- **NIH application ID:** 10399644
- **Project number:** 5R01DA051895-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** PAUL W. SPEARMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $495,301
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399644

## Citation

> US National Institutes of Health, RePORTER application 10399644, Role of Siglec-1 in HIV Interactions with Microglia and Astrocytes (5R01DA051895-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399644. Licensed CC0.

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