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TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1<jats:italic>ex vivo<\/jats:italic>. TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication<jats:italic>in vivo<\/jats:italic>.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.<\/jats:p>","DOI":"10.1128\/jvi.00430-17","type":"journal-article","created":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:40:24Z","timestamp":1497487224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1"],"prefix":"10.1128","volume":"91","author":[{"given":"Shannon M.","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brodie","family":"Miles","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejun","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Folkvord","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amie L.","family":"Meditz","sequence":"additional","affiliation":[{"name":"Beacon Center for Infectious Diseases, Boulder, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin D.","family":"McCarter","sequence":"additional","affiliation":[{"name":"Department of Surgery, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Basic Science, New York University College of Dentistry, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"MaWhinney","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario L.","family":"Santiago","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Connick","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"436","article-title":"HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy","volume":"125","author":"Biberfeld P","year":"1986","unstructured":"Biberfeld P Chayt KJ Marselle LM Biberfeld G Gallo RC Harper ME . 1986. 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