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Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity

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Abstract

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.

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Acknowledgements

Special thanks to the technical support of Caroline Côté and the Bioimaging platform of the Infectious Disease Research Centre that was funded by an equipment and infrastructure grant from the Canadian Foundation Innovation. The authors also want to thank the medical assistance of the Clinique de Planification des Naissances of the Hôpital Saint-François d’Assise.

Funding

This work was supported by funds allocated to M.J.T. from the Open Operating Grant Program of the Canadian Institutes of Health Research (CIHR) (grant no. MOP-133696). MJT is the recipient of the Tier 1 CIHR-Canada Research Chair in Human Immunoretrovirology.

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Authors and Affiliations

  1. Axe Des Maladies Infectieuses Et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Quebec, QC, G1V 4G2, Canada

    Vincent Sénécal, Corinne Barat & Michel J. Tremblay

  2. Clinique de Planification Des Naissances, CHU de Québec-Université Laval, Pavillon Hôpital Saint-François D’Assise, Quebec, QC, G1L 3L5, Canada

    Marie-Thérèse Gagnon & François Vanasse

  3. Département D’obstétrique, Gynécologie Et Reproduction, CHU de Québec-Université Laval, Pavillon CHUL, Quebec, QC, G1V 4G2, Canada

    Mathieu Leboeuf

  4. Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Quebec, QC, G1V 4G2, Canada

    David Gosselin

  5. Département de Microbiologie-Infectiologie Et Immunologie, Faculté de Médecine, Université Laval, Quebec, QC, G1V 0A6, Canada

    Michel J. Tremblay

Authors
  1. Vincent Sénécal
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  2. Corinne Barat
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  3. Marie-Thérèse Gagnon
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  4. François Vanasse
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  5. Mathieu Leboeuf
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  6. David Gosselin
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  7. Michel J. Tremblay
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Contributions

VS contributed to design the research study, conducted all the experiments, performed statistical analysis, prepared tables and figures, and wrote the manuscript; CB helped to design the experiments, data interpretation, and preparation of the manuscript. MJT supervised the study, helped to conceive the experiments, and reviewed and edited the manuscript. MTG, FV, and ML provided the fetal cerebral tissues; DG participated in the ChIP assays; all authors read and approved the final manuscript for publication.

Corresponding author

Correspondence to Michel J. Tremblay.

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Ethics approval and consent to participate

The study was approved by the Bioethics Committee at the Centre Hospitalier Universitaire de Québec-Université Laval, CHUL building (#B14-04-1973). Human fetal brain tissues from 16 to 22 weeks aborted fetuses were directly obtained from Hôpital Saint-François d’Assise or the CHUL with the written informed consent of the adult patient. Human blood samples from anonymous healthy volunteers were obtained from the CHUL with the written informed consent of each participant.

Competing interests

The authors declare that they have no conflict of interest.

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Sénécal, V., Barat, C., Gagnon, MT. et al. Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity. J. Neurovirol. 27, 279–301 (2021). https://doi.org/10.1007/s13365-021-00955-3

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