{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:45:44Z","timestamp":1782906344855,"version":"3.54.5"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Animal models are essential for defining mechanisms of HIV-associated brain injury in the antiretroviral therapy era, where neurocognitive impairment and brain aging have replaced opportunistic infections as dominant clinical concerns. Humanized mice, EcoHIV murine systems, and SIV or SHIV nonhuman primates now enable increasingly sophisticated brain imaging across\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>ex vivo<\/jats:italic>\n                    scales. Structural and diffusion MRI, perfusion imaging, manganese-enhanced MRI, and multiphoton and endoscopic optical methods provide complementary sensitivity to tissue integrity, hemodynamics, cellular dynamics, and neurovascular coupling.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    clearing and light-sheet microscopy further support whole-brain mapping and atlas-based integration with histology. We synthesize how neuroHIV imaging has progressed from structural surrogates to quantitative, multimodal pipelines and highlight a central gap for neurocognitive aging research. Longitudinal diffusion and perfusion MRI in SIV-infected macaques demonstrate that within-animal imaging can capture infection-associated trajectories. In contrast, systematic\n                    <jats:italic>in vivo<\/jats:italic>\n                    whole-brain neuroimaging remains limited in widely used murine neuroHIV models, particularly EcoHIV, despite strong behavioral and virologic phenotyping. We argue that the next phase of the field requires standardized, longitudinal, multiscale pipelines that couple high-field MRI and targeted molecular imaging with mesoscopic optical and endoscopic approaches and whole-brain three-dimensional mapping frameworks. Such integration should enable imaging-derived brain aging phenotypes in neuroHIV models, clarify mechanisms linking persistent inflammation to neurovascular and circuit dysfunction, and accelerate intervention-ready biomarkers aligned with aging cohorts of people with HIV.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1767149","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T10:50:41Z","timestamp":1782903041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Imaging the neurohiv brain in animal models: past, present, and future\u2014toward longitudinal, whole-brain aging phenotypes"],"prefix":"10.3389","volume":"18","author":[{"given":"Paddy","family":"Ssentongo","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Penn State Health Milton S. Hershey Medical Center","place":["Hershey, PA, United States"]},{"name":"Division of Epidemiology, Department of Public Health Sciences, Penn State College of Medicine","place":["Hershey, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ssentongo","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Public Health Sciences, Penn State College of Medicine","place":["Hershey, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1093\/bmb\/ldy019","article-title":"Cognitive impairment in people living with HIV in the ART era: a review","volume":"127","author":"Alford","year":"2018","journal-title":"Br. Med. Bull."},{"key":"ref2","article-title":"Development of Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) Methods to Study Pathophysiology Underlying Neurodegenerative Diseases in Murine Models. PhD Dissertation. Omaha, Nebraska, USA: University of Nebraska Medical Center","author":"Bade","year":"2015"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1007\/s12035-015-9258-3","article-title":"Manganese-enhanced magnetic resonance imaging reflects brain pathology during progressive HIV-1 infection of humanized mice","volume":"53","author":"Bade","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1007\/s00429-019-01829-5","article-title":"Individual variation in longitudinal postnatal development of the primate brain","volume":"224","author":"Ball","year":"2019","journal-title":"Brain Struct. Funct."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1038\/s41467-019-10046-x","article-title":"Targeting the HIV-infected brain to improve ischemic stroke outcome","volume":"10","author":"Bertrand","year":"2019","journal-title":"Nat. Commun."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"4546","DOI":"10.1364\/BOE.6.004546","article-title":"Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain","volume":"6","author":"Bocarsly","year":"2015","journal-title":"Biomed. Opt. Express"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/1750-1326-9-58","article-title":"Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice","volume":"9","author":"Boska","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"103995","DOI":"10.1016\/j.ebiom.2022.103995","article-title":"In vivo whole brain microvascular imaging in mice using transcranial 3D ultrasound localization microscopy","volume":"79","author":"Demeulenaere","year":"2022","journal-title":"EBioMedicine"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"100054","DOI":"10.1016\/j.bbih.2020.100054","article-title":"Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses","volume":"3","author":"Dong","year":"2020","journal-title":"Brain Behav. Immunity-Health"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41577-018-0005-7","article-title":"Nonhuman primate models of human viral infections","volume":"18","author":"Estes","year":"2018","journal-title":"Nat. Rev. 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Eng."},{"key":"ref12","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/B978-012369454-6\/50074-1","volume-title":"The Mouse in Biomedical Research","author":"Flurkey","year":"2007"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e1007061","DOI":"10.1371\/journal.ppat.1007061","article-title":"EcoHIV infection of mice establishes latent viral reservoirs in T cells and active viral reservoirs in macrophages that are sufficient for induction of neurocognitive impairment","volume":"14","author":"Gu","year":"2018","journal-title":"PLoS Pathog."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"120734","DOI":"10.1016\/j.neuroimage.2024.120734","article-title":"High-resolution diffusion magnetic resonance imaging and spatial-transcriptomic in developing mouse brain","volume":"297","author":"Han","year":"2024","journal-title":"NeuroImage"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s13365-014-0299-6","article-title":"Humanized mouse models for HIV-1 infection of the CNS","volume":"21","author":"Honeycutt","year":"2015","journal-title":"J. Neurovirol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e00222","DOI":"10.1128\/JVI.00222-18","article-title":"Central nervous system inflammation and infection during early, nonaccelerated simian-human immunodeficiency virus infection in rhesus macaques","volume":"92","author":"Hsu","year":"2018","journal-title":"J. Virol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s11904-025-00760-1","article-title":"Associations between neuroimaging measures and cognitive performance in children, adolescents, and youth living with HIV\u2014a systematic review","volume":"22","author":"Khobo","year":"2025","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"693","DOI":"10.3390\/v16050693","article-title":"EcoHIV infection of primary murine brain cell cultures to model HIV replication and neuropathogenesis","volume":"16","author":"Kim","year":"2024","journal-title":"Viruses"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"9072","DOI":"10.1038\/s41467-024-53254-w","article-title":"Developmental mouse brain common coordinate framework","volume":"15","author":"Kronman","year":"2024","journal-title":"Nat. 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Bioeng."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"3760","DOI":"10.1073\/pnas.0500649102","article-title":"A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness","volume":"102","author":"Potash","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/s41583-025-00937-y","article-title":"Three-photon microscopy: an emerging technique for deep intravital brain imaging","volume":"26","author":"Prevedel","year":"2025","journal-title":"Nat. Rev. Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"6975","DOI":"10.1021\/acs.jpcb.4c01277","article-title":"Quantitative optical imaging of oxygen in brain vasculature","volume":"128","author":"Rathbone","year":"2024","journal-title":"J. Phys. Chem. 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