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Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and\/or NF-\u03baB activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease.<\/jats:p>","DOI":"10.3390\/v18060660","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:50:58Z","timestamp":1781157058000},"page":"660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Herpesvirus-6A and -6B (HHV-6A and HHV-6B): The Role of Roseoloviruses in Neurological Dysfunction and the Mechanisms of Viral-Induced Epileptogenesis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2916-8432","authenticated-orcid":false,"given":"Elham","family":"Bahramian","sequence":"first","affiliation":[{"name":"Molecular and Cell Biology Department, University of California Merced, Merced, CA 95343, USA"},{"name":"Host-Virus Evolutionary Dynamics Institute, University of California Merced, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6116-586X","authenticated-orcid":false,"given":"Ananya","family":"Bajpai","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Department, University of California Merced, Merced, CA 95343, USA"},{"name":"Quantitative Systems Biology Program, University of California Merced, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9769-8745","authenticated-orcid":false,"given":"Xue","family":"Yang","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Department, University of California Merced, Merced, CA 95343, USA"},{"name":"Quantitative Systems Biology Program, University of California Merced, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0574-8395","authenticated-orcid":false,"given":"Dana M.","family":"Cairns","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-7774","authenticated-orcid":false,"given":"David","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-2800","authenticated-orcid":false,"given":"Ruben M.","family":"Ceballos","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Department, University of California Merced, Merced, CA 95343, USA"},{"name":"Host-Virus Evolutionary Dynamics Institute, University of California Merced, Merced, CA 95343, USA"},{"name":"Quantitative Systems Biology Program, University of California Merced, Merced, CA 95343, USA"},{"name":"Center for Interdisciplinary Neuroscience, University of California Merced, Merced, CA 95343, USA"},{"name":"Health Science Research Institute, University of California Merced, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/jcm.33.6.1660-1661.1995","article-title":"Human Herpesvirus 6 and Human Herpesvirus 7 in Chronic Fatigue Syndrome","volume":"33","author":"Zorzenon","year":"1995","journal-title":"J. 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