Variations in Aspects of Neural Precursor Cell Neurogenesis in a Human Model of HSV-1 Infection

ABSTRACT

Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

KEYWORDS:

• Herpes simplex virus 1
• human-induced pluripotent stem cells
• neural stem cells
• neural progenitor cells
• acyclovir
• brain organoids

Acknowledgments

We thank Maribeth Wesesky for the manuscript review.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Institutional review board statement

Not applicable as this study did not involve humans or animals.

Author contributions

LD: Corresponding Author: Dr. D’Aiuto conceived the study, developed the differentiation protocols to generate two-dimensional (2D) and three-dimensional (3D) neuronal cultures, performed infections with HSV-1, performed migration neurosphere formation assays and NPCs migration assays, performed immunohistochemistry analysis, data analysis and made a major contribution to the manuscript.

WZ: Contributed to the conception of the study, development of the differentiation protocols and performed HSV-1 infection, flow cytometry analysis and contributed substantially to the manuscript.

EMB, VM, PP, JC, AP: Contributed to the generation and maintenance of 2D-and 3D cultures, their infections, immunohistochemistry analysis, analysis of cell proliferation and flow cytometry analysis.

DCB, PK, VLN, JW: Participated in data analysis, critical interpretation of data and contributed significantly to manuscript preparation.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website

Additional information

Funding

This research was funded by the following funding sources: grant 1R01NS115082-01A1 from the National Institute of Neurological Disorders and Stroke (NINDS) (Leonardo D’Aiuto), 1R21NS096405-01A1 from the National Institute of Neurological Disorders and Stroke (NINDS) (Leonardo D’Aiuto), grant 5R01AI122640-05 from the National Institute of Allergy and Infectious Diseases (NIAID) (Paul R. Kinchington), grant 2P30EY008098-31 from the National Eye Institute (NEI) (Paul R. Kinchington), grants 5T32AI007110-35 and 5R01AI048633-16 from the National Institute of Allergy and Infectious Diseases (NIAID) (David C. Bloom), grant 5R01MH063480-14 from the National Institute of Mental Health (NIMH) (Vishwajit L. Nimgaonkar), and grant 07R-1712 from the Stanley Medical Research Institute (SMRI) (Vishwajit L. Nimgaonkar).