{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:02:46Z","timestamp":1782280966324,"version":"3.54.5"},"posted":{"date-parts":[[2025,2,28]]},"group-title":"Microbiology","reference-count":128,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Despite effective HIV suppression, neuroinflammation and neurocognitive issues are prevalent in people with HIV (PWH) yet poorly understood. HIV infection alters the human virome, and virome perturbations have been linked to neurocognitive issues in people without HIV. Once thought to be sterile, the cerebrospinal fluid (CSF) hosts a recently discovered virome, presenting an unexplored avenue for understanding brain and mental health in PWH. This cross-sectional study analyzed 85 CSF samples (74 from PWH on suppressive antiretroviral therapy, and 11 from controls without HIV, CWH) through shotgun metagenomics for DNA\/RNA viruses. Taxonomic composition (reads and contigs), \u03b1 and \u03b2 diversity, and relative abundance (RA) of prokaryotic (PV), human eukaryotic (hEV), and non-human eukaryotic viruses (nhEV) were evaluated in relation to HIV infection, markers of neuroinflammation and neurodegeneration, cognitive functions, and depressive symptoms. Sensitivity analyses and post-hoc cluster analysis on the RA of viral groups and blood-brain barrier permeability were also performed.<\/jats:p>\n                <jats:p>Of 46 read-positive CSF samples, 93.5% contained PV sequences, 47.8% hEV, and 45.6% nhEV. Alpha diversity was lower in PWH versus CWH, although p&gt;0.05. At \u03b2 diversity analysis, HIV status explained 3.3% of the variation in viral composition (p=0.016). Contigs retained 13 samples positive for 8 hEV, 2 nhEV, and 6 PV. Higher RA of PV was correlated with higher CSF S100\u03b2 (p=0.002) and \u03b2-Amyloid 1-42 fragment (\u03b2A-42, p=0.026), while higher RA of nhEV with poorer cognitive performance (p=0.022). Conversely, higher RA of hEV correlated with better cognition (p=0.003) and lower \u03b2A-42 (p=0.012). Sensitivity analyses in virome-positive samples only confirmed these findings. Three CSF clusters were identified and showed differences in astrocytosis, \u03b2A-42, tau protein, and cognitive functions. Participants with hEV-enriched CSF showed better cognitive performance compared to those with virus-devoid and nhEV-enriched CSF (models\u2019p&lt;0.05).<\/jats:p>\n                <jats:p>This study provides the first comprehensive description of the CSF virome in PWH, revealing associations with neuroinflammation and cognition. These findings highlight the potential involvement of the CSF virome in brain health and inform about its composition, origin, and potential clinical implications in people with and without HIV.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>HIV can affect brain health and mental well-being, even in people on successful antiretroviral therapy. The reasons behind this are still unclear. HIV also influences the communities of microbes and viruses living in the human body, and recent research suggests that the human virome, the collection of all viruses within the body, may play a role in cognitive functions, mood, and brain health. For a long time, scientists believed that the cerebrospinal fluid (CSF), which surrounds the brain, was sterile, while robust evidence has shown that the CSF hosts its own unique virome. Via advanced genetic sequencing (shotgun metagenomics), we analyzed the CSF virome in people with and without HIV looking for possible links to neuroinflammation, cognitive performance, and depression. We found that while HIV infection does affect the composition of CSF viral communities, there were no remarkable differences in the CSF virome of individuals with and without HIV. Most viral sequences appeared to come outside the brain. A higher abundance of non-human viral sequences, such as viruses of bacteria, plants, fungi, and animals, was associated with neuroinflammation and poorer cognitive performance. On the other hand, a higher abundance of human viruses correlated with better cognitive function and healthier signature of neuromarkers. These findings provide new insights into the presence and characteristics of the human CSF virome and how it might influence brain health. They also suggest new potential mechanisms of HIV-associated neuropathology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.28.640732","type":"posted-content","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T21:35:13Z","timestamp":1740778513000},"source":"Crossref","is-referenced-by-count":0,"title":["The cerebrospinal fluid virome in people with HIV: links to neuroinflammation and cognition"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-719X","authenticated-orcid":false,"given":"Mattia","family":"Trunfio","sequence":"first","affiliation":[{"name":"Unit of Infectious Diseases, Amedeo di Savoia hospital, Department of Medical Sciences, University of Turin, Turin 10149, Italy"},{"name":"HIV Neurobehavioral Research Program, Departments of Neurosciences and Psychiatry, University of California San Diego, CA 92103, USA"},{"name":"Division of Infectious Diseases and Global Health, Department of Medicine, University of California San Diego, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Scutari","sequence":"additional","affiliation":[{"name":"Multimodal Laboratory Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, Rome 00165, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Fox","sequence":"additional","affiliation":[{"name":"Multimodal Laboratory Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, Rome 00165, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Vuaran","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Amedeo di Savoia hospital, Department of Medical Sciences, University of Turin, Turin 10149, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raha Maryam","family":"Dastgheyb","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Fini","sequence":"additional","affiliation":[{"name":"Multimodal Laboratory Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, Rome 00165, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Granaglia","sequence":"additional","affiliation":[{"name":"Multimodal Laboratory Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, Rome 00165, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Balbo","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Amedeo di Savoia hospital, Department of Medical Sciences, University of Turin, Turin 10149, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora","family":"Tortarolo","sequence":"additional","affiliation":[{"name":"Department of Informatics, University of Turin, Turin 10149, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Bonora","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Amedeo di Savoia hospital, Department of Medical Sciences, University of Turin, Turin 10149, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo Federico","family":"Perno","sequence":"additional","affiliation":[{"name":"Multimodal Laboratory Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, Rome 00165, Italy"},{"name":"UniCamillus International Medical University, Rome 00131, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Di Perri","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Amedeo di Savoia 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