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significant neurodevelopmental deficits in the unborn\/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.<\/jats:p>","DOI":"10.3390\/cells11223539","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T02:03:58Z","timestamp":1668045838000},"page":"3539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids"],"prefix":"10.3390","volume":"11","author":[{"given":"Leonardo","family":"D\u2019Aiuto","sequence":"first","affiliation":[{"name":"Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O\u2019Hara Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O\u2019Hara Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callen T.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Medicine, University of Pittsburgh, 3500 Terrace Street, S362 Biomedical Science Tower (South), Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-3745","authenticated-orcid":false,"given":"Tristan R.","family":"Grams","sequence":"additional","affiliation":[{"name":"Academic Research Building, Department of Molecular Genetics and Microbiology, University of Florida, 1200 Newell Drive, R2-231, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maribeth A.","family":"Wesesky","sequence":"additional","affiliation":[{"name":"Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O\u2019Hara Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel A.","family":"Wood","sequence":"additional","affiliation":[{"name":"Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O\u2019Hara Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon C.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Medicine, University of Pittsburgh, 3500 Terrace Street, S362 Biomedical Science Tower (South), Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1901-9970","authenticated-orcid":false,"given":"Paul R.","family":"Kinchington","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh, Suite 820, Eye & Ear Building, 203 Lothrop Street, Pittsburgh, PA 15213, USA"},{"name":"Department of Molecular Genetics and Microbiology, School of Medicine, University of Pittsburgh, 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Academic Research Building, Department of Molecular Genetics and Microbiology, University of Florida, 1200 Newell Drive, R2-231, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishwajit L.","family":"Nimgaonkar","sequence":"additional","affiliation":[{"name":"Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O\u2019Hara Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"390","DOI":"10.3200\/JRLP.143.4.390-404","article-title":"Psychosocial correlates and outcomes of yoga or walking among older adults","volume":"143","author":"Kraemer","year":"2009","journal-title":"J. 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