HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model

Author:

Min Alice K.1ORCID,Javidfar Behnam23,Missall Roy3,Doanman Donald1,Durens Madel4,Graziani Mara3,Mordelt Annika56,Marro Samuele G.4,de Witte Lotje356,Chen Benjamin K.1ORCID,Swartz Talia H.1ORCID,Akbarian Schahram23ORCID

Affiliation:

1. Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA

2. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA

4. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

5. Department of Human Genetics and Department of Cognitive Neuroscience, Radboud UMC, Nijmegen, the Netherlands

6. Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands

Abstract

ABSTRACT The central nervous system (CNS) is a major human immunodeficiency virus type-1 (HIV-1) reservoir. Microglia are the primary target cell of HIV-1 infection in the CNS. Current models have not allowed the precise molecular pathways of acute and chronic CNS microglial infection to be tested with in vivo genetic methods. Here, we describe a novel-humanized mouse model utilizing human induced pluripotent stem cell (iPSC)-derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that serve as a medium to establish a peripheral infection that then spreads to the CNS microglia xenograft, modeling a trans-blood-brain barrier route of acute CNS HIV-1 infection with human target cells. The approach is compatible with iPSC genetic engineering, including inserting targeted transgenic reporter cassettes to track the xenografted human cells, enabling the testing of novel treatment and viral tracking strategies in a comparatively simple and cost-effective in vivo model for neuroHIV. IMPORTANCE Our mouse model is a powerful tool for investigating the genetic mechanisms governing central nervous system (CNS) human immunodeficiency virus type-1 (HIV-1) infection and latency in the CNS at a single-cell level. A major advantage of our model is that it uses induced pluripotent stem cell-derived microglia, which enables human genetics, including gene function and therapeutic gene manipulation, to be explored in vivo , which is more challenging to study with current hematopoietic stem cell-based models for neuroHIV. Our transgenic tracing of xenografted human cells will provide a quantitative medium to develop new molecular and epigenetic strategies for reducing the HIV-1 latent reservoir and to test the impact of therapeutic inflammation-targeting drug interventions on CNS HIV-1 latency.

Funder

HHS | NIH | National Institute on Drug Abuse

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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