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Neuroinflammatory crosstalk between microglia and astrocytes increases viral replication in an iPSC-derived model of CNS HIV infection
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  • Published: 11 March 2026

Neuroinflammatory crosstalk between microglia and astrocytes increases viral replication in an iPSC-derived model of CNS HIV infection

  • James Gesualdi1,
  • Jude Prah2,
  • Shiden Solomon2,
  • Jayden Cyrus2,
  • Ernesto Baçi3,
  • Peter J Gaskill4,
  • Çagla Akay-Espinoza2 &
  • …
  • Kelly L. Jordan-Sciutto2 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Diseases
  • Immunology
  • Microbiology
  • Neuroscience

Abstract

People living with HIV suffer multiple comorbid conditions related to chronic inflammation at increased rates compared to the general population, even when on effective antiretroviral therapy. In particular, current data indicate that the increased incidence and severity of neurocognitive impairment (NCI) are associated with unresolved neuroinflammation. Attempts to treat NCI in people living with HIV by reducing inflammation have thus far been unsuccessful, suggesting that a more mechanistic understanding of inflammatory processes in the CNS during HIV is necessary. Here, we use iPSC-derived microglia (iMg) and astrocytes (iAst) to model HIV infection in the CNS. We show that our iMg robustly express markers associated with microglial identity and are susceptible to HIV infection, but exhibit lower HIV replication rates and weaker immune response to HIV challenge compared to monocyte-derived macrophages. Coculture of iAst with iMg leads to a much stronger pro-inflammatory immune response, and, surprisingly, a robust increase in rates of HIV replication. Increased replication in iMg/iAst cocultures is associated with higher levels of multiple pro-inflammatory cytokines, including TNFα, which is produced by iAst upon exposure to HIV-infected iMg. Addition of exogenous TNFα to iMg during HIV infection is also sufficient to increase rates of replication, and neutralization of TNFα via adalimumab/Humira treatment in iMg/iAst cocultures reduces replication. Blocking NF-kB signaling with iKK inhibitor Bay-11-7082 (Bay-11) demonstrates that increased HIV replication in iMg/iAst cocultures is due to increased NF-kB activity. Finally, we show that in HIV-infected iMg there is movement of lysosomes to the periphery of the cell membrane and release of lysosomal content into the extracellular space, suggesting that this dysregulated lysosomal flux could further contribute to the pro-inflammatory microenvironment. We propose that this altered lysosomal trafficking and increased cytokine production drives a pro-inflammatory phenotype in glia and represents a potential source of unresolved neuroinflammation in people living with HIV.

Data availability

All sequencing data are available in the NCBI GEO database (https://www.ncbi.nlm.nih.gov/geo/) with the accession number GSE143685. Other data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

HIV:

Human Immunodeficiency virus

NCI:

Neurocognitive impairment

HAND:

HIV-associated neurocognitive disorder

HABI:

HIV-associated brain injury

PLWH:

People living with HIV

ART:

Anti-retroviral therapy

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

iPSCs:

Induced pluripotent stem cells

iMg:

iPSC-derived microglia

iAst:

iPSC-derived astrocytes

CC:

Coculture

CM:

Conditioned media

MDM:

Monocyte-derived macrophages

CMP:

Common myeloid progenitor

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Acknowledgments

We would like to thank all the members of the Gaskill lab and myeloid working group for invaluable discussion on the data. The authors thank Max Eldabbas, Emileigh Maddox, Tanishk Sinha, and Jiayi Shu of the Human Immunology Core at the Perelman School of Medicine at the University of Pennsylvania for assistance with isolation and differentiation of primary human monocytes. The HIC is supported in part by NIH P30 AI045008 and P30 CA016520. The following reagent was obtained through the NIH HIV Reagent Program, NIAID, NIH: Monoclonal Anti-Human Immunodeficiency Virus Type 1 (HIV-1) p24 Gag protein, Clone AG3.0 (produced in vitro), HRP-20068, contributed by Creative Biolabs.

Funding

This research was funded by the National Institutes of Health grant no. T32 (JG), F31 MH131486(JG), R01DA057337(PJG), R61DA058501 (PJG), R21MH129193 (CAE), R01DA049514 and R01DA052826 (KLJS), and P30AI045008 (KJS, CAE).

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Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, US

    James Gesualdi

  2. School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, US

    Jude Prah, Shiden Solomon, Jayden Cyrus, Çagla Akay-Espinoza & Kelly L. Jordan-Sciutto

  3. School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, US

    Ernesto Baçi

  4. Department of Pharmacology and Physiology, Drexel University, Philadelphia, PA, US

    Peter J Gaskill

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JG, CAE, and KLJS contributed study conceptualization and methodology. JG, JP, SS, EB, JS contributed experimental design, data acquisition, and data analysis. JG contributed original draft preparation. All authors contributed to writing, review, and editing. JG, PJG, CAE, and KJS contributed funding. All authors have read and agreed to the submitted version of the manuscript.

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Gesualdi, J., Prah, J., Solomon, S. et al. Neuroinflammatory crosstalk between microglia and astrocytes increases viral replication in an iPSC-derived model of CNS HIV infection. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43248-7

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  • Received: 19 September 2025

  • Accepted: 03 March 2026

  • Published: 11 March 2026

  • DOI: https://doi.org/10.1038/s41598-026-43248-7

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Scientific Reports (Sci Rep)

ISSN 2045-2322 (online)

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