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This is signified by increased numbers of exhausted CD21neg memory B cells, driven by continuous antigen-specific and bystander activation. Using high-dimensional flow cytometry, we demonstrate that this exhausted phenotype is also prevalent among peripheral antigen-inexperienced naive and marginal zone (MZ) B cells in acute and chronic HIV-1 infection. A substantial fraction of naive and MZ B cells exhibit down-regulated CD21 levels and diminished response to B cell receptor (BCR)\u2013dependent stimulation. Compared with CD21pos subsets, the CD21neg naive and MZ B cells differ in the expression of chemokine receptors and activation markers. Effective antiretroviral treatment normalizes peripheral naive and MZ B cell populations. Our results emphasize a more widely spread impairment of B cells in HIV-1 infection than previously appreciated, including antigen-inexperienced cells. This highlights the importance of monitoring functional capacities of naive B cells in HIV-1 infection, as exhausted CD21neg naive B cells may severely impair induction of novel B cell responses.<\/jats:p>","DOI":"10.1084\/jem.20181124","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T18:55:20Z","timestamp":1561056920000},"page":"2071-2090","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-6679","authenticated-orcid":true,"given":"Thomas","family":"Liechti","sequence":"first","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Kadelka","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4036-1030","authenticated-orcid":true,"given":"Dominique L.","family":"Braun","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6873-0091","authenticated-orcid":true,"given":"Herbert","family":"Kuster","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7925-4852","authenticated-orcid":true,"given":"J\u00fcrg","family":"B\u00f6ni","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3570-8255","authenticated-orcid":true,"given":"Melissa","family":"Robbiani","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Population Council, New York, NY 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-6723","authenticated-orcid":true,"given":"Huldrych F.","family":"G\u00fcnthard","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"},{"name":"Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1013-876X","authenticated-orcid":true,"given":"Alexandra","family":"Trkola","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,6,20]]},"reference":[{"key":"2023072822271163700_bib1","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.it.2006.09.006","article-title":"Bystander T cell activation-implications for HIV infection and other diseases","volume":"27","author":"Bangs","year":"2006","journal-title":"Trends Immunol."},{"key":"2023072822271163700_bib2","doi-asserted-by":"publisher","first-page":"5800","DOI":"10.1128\/JVI.00094-13","article-title":"Characterization of plasmablasts in the blood of HIV-infected viremic individuals: evidence for nonspecific immune activation","volume":"87","author":"Buckner","year":"2013","journal-title":"J. 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